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Kanda T, Okamoto H. Thermal Inactivation of Hepatitis E Virus: A Narrative Review. Viruses 2025; 17:702. [PMID: 40431713 PMCID: PMC12115974 DOI: 10.3390/v17050702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/12/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatitis E virus (HEV) infection is an emerging infectious disease. HEV-1 and HEV-2 infect humans through contaminated water and foods, mainly in developing countries. HEV-3 and HEV-4 also infect humans through contaminated food and are thought to be zoonotic infections occurring in both developing and developed countries. A vaccine for hepatitis E is licensed in only limited countries. The inactivation of infectious HEV is very important to ensure the safety of drinking water and foods. HEV-3 and HEV-4 RNA have been detected in some pig liver products, and it is possible that these foods may represent an infectious source of HEV. In this article, previous publications on the heat inactivation and heat stability of HEV are collected, and we discuss the present assessment of the heat inactivation of HEV. The thermal stability of HEV infection in cell culture systems and pig bioassays has been demonstrated, while the efficacy of the method of thermal inactivation using plasma products has not yet been established. Here, we propose that the treatment of HEV-contaminated foods at 95 °C for 10 min is one of the safest options for the inactivation of HEV.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Minami-Uonuma 949-7302, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan;
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Sasaki-Tanaka R, Kanda T, Yokoo T, Abe H, Hayashi K, Sakamaki A, Kamimura H, Terai S. Hepatitis A and E Viruses Are Important Agents of Acute Severe Hepatitis in Asia: A Narrative Review. Pathogens 2025; 14:454. [PMID: 40430774 PMCID: PMC12114595 DOI: 10.3390/pathogens14050454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/25/2025] [Accepted: 05/03/2025] [Indexed: 05/29/2025] Open
Abstract
Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are severe hepatitis that occur in patients with and without chronic liver diseases and/or cirrhosis, respectively, and both often result in death. Hepatitis A virus (HAV) and hepatitis E virus (HEV) infection can cause these severe conditions. We reviewed the role of HAV and HEV, which infect humans through the fecal-oral route, in ALF and ACLF in Asian countries. This narrative review was the derived from a traditional non-systematic review. Hepatitis A should be recognized as one of the sexually transmitted infections, especially among men who have sex with men. HAV genotype IIIA infection seems to present a more severe clinical manifestation. Acute HEV-1 infection is associated with ALF in pregnant women in India. HEV-4, rather than HEV-3, was found in severe hepatitis in Japan. HEV also plays a role as a cause of acute insult and/or chronic liver disease in immunocompromised patients with ACLF. Further studies are needed for the development of vaccines and antivirals against HAV and HEV infections. Despite the limitations of the recording of cases and the extent of specific vaccinations, multidisciplinary cooperation, involving hepatologists, virologists, experts in public health, etc., may improve the treatment of HAV and HEV infection.
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Affiliation(s)
- Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Minami-Uonuma, Niigata 949-7302, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan; (R.S.-T.); (T.Y.); (H.A.); (K.H.); (A.S.); (H.K.); (S.T.)
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Pavlova A, Kocikova B, Dolinska MU, Jackova A. Hepatitis E Virus in the Role of an Emerging Food-Borne Pathogen. Microorganisms 2025; 13:885. [PMID: 40284721 PMCID: PMC12029509 DOI: 10.3390/microorganisms13040885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/04/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025] Open
Abstract
Viral hepatitis E represents an important global health problem caused by the hepatitis E virus (HEV). Cases of HEV infection are increasingly associated with food-borne transmissions after the consumption of raw or undercooked food products from infected animals in high-income regions. Although most cases of infection are asymptomatic, severe courses of infection have been reported in specific groups of people, predominantly among pregnant women and immunocompromised patients. The viral nucleic acid of HEV is increasingly being reported in food-producing animals and different products of an animal origin. Even though the incubation period for HEV infection is long, several direct epidemiological links between human cases and the consumption of HEV-contaminated meat and meat products have been described. In this article, we review the current knowledge on human HEV infections, HEV in different food-producing animals and products of an animal origin, as well as the accumulation and resistance to HEV in farm and slaughterhouse environments. We also provide preventive measures to help eliminate HEV from animals, the human population, and the environment.
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Affiliation(s)
| | | | | | - Anna Jackova
- Department of Epizootiology, Parasitology and Protection of One Health, University of Veterinary Medicine and Pharmacy in Kosice, Komenskeho 73, 041 81 Kosice, Slovakia; (A.P.); (B.K.); (M.U.D.)
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Daniel R, Zelber-Sagi S, Barak M, Zuckerman E. The Epidemiology of Hepatitis E in Israel and Potential Risk Factors: A Cross-Sectional Population-Based Serological Survey of Hepatitis E Virus in Northern Israel. Viruses 2025; 17:536. [PMID: 40284979 PMCID: PMC12031424 DOI: 10.3390/v17040536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatitis E Virus (HEV) has gained public health attention as one of the causative agents of viral hepatitis. Our study aimed to provide data about HEV seropositivity in the Israeli general population, including its seroprevalence geographical distribution, and to identify variables as possible risk factors for HEV exposure. A seroprevalence cross-sectional study was conducted: HEV serological status was determined in 716 blood samples collected from the routine check-up blood samples. Demographic information was available for all samples. The overall prevalence of HEV IgG in an apparently healthy population in the north of Israel was 10.5%, with no evidence of positive HEV IgM. There was a significant association between HEV seropositivity and elderly age and low socioeconomic status (SES). The age-adjusted seroprevalence was significantly lower among Jews compared to Arabs with a rate ratio of 2.02. We identified clusters (hot spots) of HEV infection in three regions under study. Our results confirmed a high prevalence of anti-HEV in the country where clinical hepatitis E is not endemic. For the first time, this study showed that a hot spot analysis was able to provide new knowledge about actual exposure zones. As HEV infection is not a notifiable disease, it is probably underdiagnosed. Thus, better awareness among physicians is warranted.
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Affiliation(s)
- Rasha Daniel
- Haifa and Western Galilee Central Laboratories, Clalit Health Services, Nesher 20300, Israel
| | - Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel;
| | - Mira Barak
- Head of Medical Laboratory Sciences, Zefat Academic College, Safed 13206, Israel;
| | - Eli Zuckerman
- Liver Unit, Carmel Medical Center, Faculty of Medicine, Technion Institute, Haifa 3498838, Israel
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Baymakova MP, Konaktchieva M, Kunchev M, Popivanov G, Kundurzhiev T, Tsachev I, Mutafchiyski V. First Insight into the Seroprevalence of Hepatitis E Virus and Associated Risk Factors Among Liver Transplant Recipients from Bulgaria. Vector Borne Zoonotic Dis 2025; 25:303-313. [PMID: 39943906 DOI: 10.1089/vbz.2024.0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2025] Open
Abstract
Introduction: Hepatitis E virus (HEV) infection is caused by viruses belonging to the Hepeviridae family. HEV infection can be self-limiting; however, extrahepatic manifestations may be present. The purpose of the current study was to establish the seroprevalence of HEV among Bulgarian liver transplant recipients (LTRs) and to identify associated risk factors. Materials & Methods: The present study was conducted between April 1, 2023, and October 30, 2023, at the Military Medical Academy, Sofia, Bulgaria. All serum samples were tested for anti-HEV IgG/IgM using HEV IgG/IgM enzyme-linked immunosorbent assay on Dia.Pro (Milan, Italy). Each participating LTR completed a detailed paper-based closed-ended questionnaire regarding the associated risk factors for HEV infection. Results: The study included 73 LTRs with a mean age of 47.0 ± 14.0 years. Anti-HEV IgG antibodies were detected in 25 LTRs (34.2%), including 20 males (37.7%) and 5 females (25%). All participants were HEV-IgM negative. HEV seropositivity rates were higher but not statistically significant in LTRs aged >60 years than in those aged <60 years (40% vs. 32.7%). A significant factor by logistic regression was "high level of education" (odds ratio [OR] = 2.917; p = 0.038). Conclusion: To the best of our knowledge, this is the first seroepidemiological HEV study among LTRs from Bulgaria that found a high seroprevalence (34.2%).
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Affiliation(s)
| | - Marina Konaktchieva
- Department of Gastroenterology and Hepatology, Military Medical Academy, Sofia, Bulgaria
| | - Metodi Kunchev
- Department of Virology, Military Medical Academy, Sofia, Bulgaria
| | - Georgi Popivanov
- Department of Surgery, Military Medical Academy, Sofia, Bulgaria
| | - Todor Kundurzhiev
- Department of Occupational Medicine, Faculty of Public Health, Medical University, Sofia, Bulgaria
| | - Ilia Tsachev
- Department of Microbiology, Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
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León-Janampa N, Brand D, Marlet J. [Hepatitis E: Epidemiology, pathology and prevention]. Med Sci (Paris) 2025; 41:346-354. [PMID: 40294294 DOI: 10.1051/medsci/2025047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025] Open
Abstract
Hepatitis E virus (HEV) is a major cause of acute hepatitis. HEV genotypes 1 and 2 are associated with oro-faecal epidemics and fulminant hepatitis in pregnant women. HEV genotypes 3 and 4 are a zoonosis transmitted by uncooked pork. Infection is usually spontaneously resolutive. Chronic hepatitis may occur in immunocompromised patients. Extrahepatic disease is also possible. Prevention is based on hygiene, especially in high-risk patients, and access to safe drinking water for all. A recombinant vaccine against HEV has been developed and is currently being validated by the WHO.
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Affiliation(s)
- Nancy León-Janampa
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
| | - Denys Brand
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
| | - Julien Marlet
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
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Binda B, Picchi G, Bruni R, Di Gasbarro A, Madonna E, Villano U, Pisani G, Carocci A, Marcantonio C, Montali F, Panarese A, Pisani F, Ciccaglione AR, Spada E. The Prevalence, Risk Factors, and Outcomes of Hepatitis E Virus Infection in Solid Organ Transplant Recipients in a Highly Endemic Area of Italy. Viruses 2025; 17:502. [PMID: 40284945 PMCID: PMC12031106 DOI: 10.3390/v17040502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatitis E virus (HEV) infection can become chronic in immunocompromised patients, like solid organ transplant recipients (SOTRs). We evaluated HEV prevalence, risk factors, and outcomes among SOTRs in a hyperendemic HEV area. Three hundred SOTRs were enrolled from April to July 2019 and tested for anti-HEV IgM and IgG and HEV RNA. Sixty-three recipients (21%) were positive for any HEV marker. HEV infection was independently associated with older age and pork liver sausage consumption. Three viremic recipients harbored genotype 3e and 3f according to HEV RNA sequencing and phylogenetic analysis. Overall, 10 recipients had markers of active/recent infection (HEV RNA and/or anti-HEV IgM) and were followed up prospectively. Five of them spontaneously resolved their HEV infection. In two recipients, HEV clearance was achieved only through immunosuppression reduction, while three needed ribavirin therapy to achieve virologic resolution. We observed a chronic course in 30% of SOTRs with active/recent HEV infection. No association was found between tacrolimus assumption and chronicization. In conclusion, we found a high prevalence of infection among SOTRs attending a transplant center in a hyperendemic Italian HEV region. Systematic screening for all HEV markers and dietary education for infection control are needed for transplant recipients.
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Affiliation(s)
- Barbara Binda
- General and Transplant Surgery Department, San Salvatore Hospital, 67100 L’Aquila, Italy;
| | - Giovanna Picchi
- Department of Clinical Medicine, Life, Health and Environmental Sciences-MESVA, University of L’Aquila, 67100 L’Aquila, Italy
- Infectious Diseases Department, ASL VT, PO Ospedale Belcolle Santa Rosa, 01100 Viterbo, Italy
| | - Roberto Bruni
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
| | - Alessandro Di Gasbarro
- Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy;
| | - Elisabetta Madonna
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
| | - Umbertina Villano
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
| | - Giulio Pisani
- National Center for the Control and Evaluation of Medicines, Istituto Superiore di Sanita, 00161 Rome, Italy; (G.P.); (A.C.)
| | - Alberto Carocci
- National Center for the Control and Evaluation of Medicines, Istituto Superiore di Sanita, 00161 Rome, Italy; (G.P.); (A.C.)
| | - Cinzia Marcantonio
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
| | - Filippo Montali
- General and Transplant Surgery Department, Dipartimento di Scienze Cliniche Applicate e Biotecnologiche-DISCAB, University of L’Aquila, 67100 L’Aquila, Italy; (F.M.); (A.P.); (F.P.)
| | - Alessandra Panarese
- General and Transplant Surgery Department, Dipartimento di Scienze Cliniche Applicate e Biotecnologiche-DISCAB, University of L’Aquila, 67100 L’Aquila, Italy; (F.M.); (A.P.); (F.P.)
| | - Francesco Pisani
- General and Transplant Surgery Department, Dipartimento di Scienze Cliniche Applicate e Biotecnologiche-DISCAB, University of L’Aquila, 67100 L’Aquila, Italy; (F.M.); (A.P.); (F.P.)
| | - Anna Rita Ciccaglione
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
| | - Enea Spada
- Department of Infectious Diseases, Istituto Superiore di Sanita, 00161 Rome, Italy; (R.B.); (E.M.); (U.V.); (C.M.); (A.R.C.); (E.S.)
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Haller IE, Reinwald M, Kah J, Eggert FAM, Schwarzlose-Schwarck S, Jahnke K, Lüth S, Dammermann W. Low Serological Agreement of Hepatitis E in Immunocompromised Cancer Patients: A Comparative Study of Three Anti-HEV Assays. Antibodies (Basel) 2025; 14:27. [PMID: 40265408 PMCID: PMC12015928 DOI: 10.3390/antib14020027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/12/2025] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND/OBJECTIVES Hepatitis E virus (HEV) is one of the leading causes of acute hepatitis, with immunosuppressed individuals, such as oncology patients, being particularly vulnerable to chronic infections that may progress to liver disease or fatal outcomes. Assay variability complicates HEV prevalence assessment in at-risk groups. This study aimed to compare the reliability and concordance of three HEV antibody assays-Wantai, Euroimmun, and Elecsys®-in immunosuppressed oncology patients. METHODS In this prospective pilot study, serum samples were obtained from oncology patients between September 2020 and October 2021. Samples were collected both at baseline (treatment-naive) and during ongoing treatment. A healthy control group was retrospectively included for comparative analysis. Anti-HEV IgM and IgG antibodies were tested in all samples using enzyme-linked immunosorbent assays (Wantai, Euroimmun) and an electrochemiluminescence immunoassay (Elecsys®). Demographic and clinical data, along with information on HEV risk factors, were extracted from medical records and patient questionnaires. RESULTS HEV IgM prevalence ranged from 0% (Wantai) to 6% (Elecsys®), while IgG prevalence was 12% (Euroimmun), 38% (Wantai), and 53% (Elecsys®). Concordance was poor, with Cohen's Kappa values indicating slight to moderate agreement (κ = 0.000-0.553). Patients with hematological malignancies exhibited the highest IgG seroprevalence. Risk factor analysis revealed the highest association between HEV exposure and the consumption of undercooked pork or crop-based agriculture. CONCLUSIONS Significant variability among HEV serological assays highlights the challenges of reliable HEV diagnostics in immunosuppressed oncology patients. Assay selection and improved testing strategies are critical for this high-risk group.
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Affiliation(s)
- Isabel-Elena Haller
- Department of Gastroenterology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Mark Reinwald
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam,14469 Potsdam, Germany
- Department of Hematology and Oncology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Janine Kah
- Department of Gastroenterology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Franz A. M. Eggert
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam,14469 Potsdam, Germany
- Department of Neurosurgery, School for Mental Health and Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Sandra Schwarzlose-Schwarck
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam,14469 Potsdam, Germany
- Department of Hematology and Oncology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Kristoph Jahnke
- Oncology Specialist Practice Brandenburg, 14772 Brandenburg an der Havel, Germany
| | - Stefan Lüth
- Department of Gastroenterology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Werner Dammermann
- Department of Gastroenterology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
- Center of Translational Medicine, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
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Zhang F, Xu LD, Wu S, Wu Q, Wang A, Liu S, Zhang Q, Yu X, Wang B, Pan Y, Huang F, Neculai D, Xia B, Feng XH, Shen L, Zhang Q, Liang T, Huang YW, Xu P. Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis. Proc Natl Acad Sci U S A 2025; 122:e2419946122. [PMID: 40073055 PMCID: PMC11929459 DOI: 10.1073/pnas.2419946122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin-proteasomal processing leading to formation of the HEV-Derived SMAD Activator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection-induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host-HEV interaction that facilitates hepatitis E pathogenesis.
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Affiliation(s)
- Fei Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou311215, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Ling-Dong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
- Laboratory Animal Center, Zhejiang University, Hangzhou310058, China
| | - Shiying Wu
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou310018, China
| | - Qirou Wu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Ailian Wang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Shengduo Liu
- Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou311215, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Qian Zhang
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Xinyuan Yu
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Bin Wang
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou510642, China
| | - Yinghao Pan
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Fei Huang
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Dante Neculai
- Department of Cell Biology Zhejiang University School of Medicine, Hangzhou310058, China
| | - Bing Xia
- Department of Thoracic Cancer, Affiliated Hangzhou Cancer Hospital, Westlake University, Hangzhou310030, China
| | - Xin-Hua Feng
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
- Cancer Center Zhejiang University, Hangzhou310058, China
| | - Li Shen
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Cancer Center Zhejiang University, Hangzhou310058, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Cancer Center Zhejiang University, Hangzhou310058, China
| | - Yao-Wei Huang
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou510642, China
| | - Pinglong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310058, China
- Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou311215, China
- Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou310058, China
- Cancer Center Zhejiang University, Hangzhou310058, China
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10
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Hu X, Wang J, Wang Y, Liu L, Miao J, Ren H, Wang J, Xu X. Uncovering the Prevalence and Genetic Characterization of Rabbit-Derived Paslahepevirus Balayani (Hepatitis E Virus) in Hebei Province, China. FOOD AND ENVIRONMENTAL VIROLOGY 2025; 17:20. [PMID: 40032702 DOI: 10.1007/s12560-025-09636-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
Paslahepevirus balayani (hepatitis E virus) is a zoonotic pathogen, with rabbit Paslahepevirus balayani (HEV-3ra) being widely distributed among global rabbit populations. Notably, in China, rabbits constitute a significant HEV host, second only to swine. Emerging evidence suggests that HEV-3ra possesses the capability to cross species barriers and infect humans. Against this backdrop, our investigation aimed to delineate the HEV infection status and epidemiological patterns in the commercial rabbits of Hebei Province, China. We collected 386 liver and 100 fecal samples across four regions in Hebei Province. Detection of HEV RNA in these specimens was achieved by employing reverse transcription quantitative polymerase chain reaction (RT-qPCR) and reverse transcription nested PCR (RT-Nested PCR), focusing on the amplification of a segment of the open reading frame 2 (ORF2) and the complete genome. Among the 486 samples, 73 were tested positive for HEV RNA, resulting in an overall positive rate of 15.0%. The positive rates for liver and fecal samples were 11.7% (45/386) and 28.0% (28/100), respectively. The study successfully obtained 38 partial ORF2 sequences and 5 complete genome sequences. Sequence analysis revealed that the complete genome sequences shared 86.0-94.5% nucleotide identity with HEV-3ra sequences in GenBank. Phylogenetic analysis confirmed that all strains belonged to HEV-3ra and were closely related to previously reported sequences from China. This study provides the first comprehensive genomic overview of circulating HEV-3ra strains in Hebei, offering valuable insights into the infection dynamics and prevalence of HEV-3ra among commercial rabbits, which can inform public health strategies.
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Affiliation(s)
- Xinyue Hu
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Jinfeng Wang
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
| | - Yinuo Wang
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Libing Liu
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
| | - Junjie Miao
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Huan Ren
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Jianchang Wang
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017.
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051.
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017.
| | - Xiangdong Xu
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017.
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017.
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11
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Mallet V, Torres HA. Hepatitis E virus infection after CAR T-cell treatment: An important complication in patients already facing significant health challenges. Br J Haematol 2025; 206:1020-1021. [PMID: 39622628 DOI: 10.1111/bjh.19931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 03/08/2025]
Abstract
Cancer patients with haematological malignancies are at risk for chronic hepatitis E virus infection following chimeric antigen receptor (CAR) T-cell therapy. Strong clinical suspicion is essential for the early diagnosis and prompt treatment of this difficult-to-treat type of viral hepatitis. Commentary on: Schwarz et al. Chronic hepatitis E in a patient after CAR-T cell treatment for diffuse large B-cell lymphoma and rapid progression towards decompensated liver cirrhosis. Br J Haematol 2025; 206:977-980.
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Affiliation(s)
- Vincent Mallet
- Service Hépatologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris Université Paris Cité, Paris, France
| | - Harrys A Torres
- Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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12
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Ssebyatika G, Dinkelborg K, Ströh LJ, Hinte F, Corneillie L, Hueffner L, Guzman EM, Nankya PL, Plückebaum N, Fehlau L, Garn J, Meyer N, Prallet S, Mehnert AK, Kraft ARM, Verhoye L, Jacobsen C, Steinmann E, Wedemeyer H, Viejo-Borbolla A, Dao Thi VL, Pietschmann T, Lütgehetmann M, Meuleman P, Dandri M, Krey T, Behrendt P. Broadly neutralizing antibodies isolated from HEV convalescents confer protective effects in human liver-chimeric mice. Nat Commun 2025; 16:1995. [PMID: 40011441 PMCID: PMC11865592 DOI: 10.1038/s41467-025-57182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/12/2025] [Indexed: 02/28/2025] Open
Abstract
Hepatitis E virus (HEV) causes 3.3 million symptomatic cases and 44,000 deaths per year. Chronic infections can arise in immunocompromised individuals, and pregnant women may suffer from fulminant disease as a consequence of HEV infection. Despite these important implications for public health, no specific antiviral treatment has been approved to date. Here, we report combined functional, biochemical, and X-ray crystallographic studies that characterize the human antibody response in convalescent HEV patients. We identified a class of potent and broadly neutralizing human antibodies (bnAbs), targeting a quaternary epitope located at the tip of the HEV capsid protein pORF2 that contains an N-glycosylation motif and is conserved across members of the Hepeviridae. These glycan-sensitive bnAbs specifically recognize the non-glycosylated pORF2 present in infectious particles but not the secreted glycosylated form acting as antibody decoy. Our most potent bnAb protects human liver-chimeric mice from intraperitoneal HEV challenge and co-housing exposure. These results provide insights into the bnAb response to this important emerging pathogen and support the development of glycan-sensitive antibodies to combat HEV infection.
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Affiliation(s)
- George Ssebyatika
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Katja Dinkelborg
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
| | - Luisa J Ströh
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Florian Hinte
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Corneillie
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lucas Hueffner
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Elina M Guzman
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Prossie L Nankya
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Nina Plückebaum
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Lukas Fehlau
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Jonathan Garn
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Nele Meyer
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Sarah Prallet
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Ann-Kathrin Mehnert
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Carina Jacobsen
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Abel Viejo-Borbolla
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Viet Loan Dao Thi
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Thomas Pietschmann
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Braunschweig, Germany
- University Medical Center Hamburg-Eppendorf, Institute of Medical Microbiology, Virology and Hygiene, Hamburg, Germany
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Maura Dandri
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Krey
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany.
- German Center for Infection Research (DZIF), Braunschweig, Germany.
- Institute of Virology, Hannover Medical School, Hannover, Germany.
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
- Centre for Structural Systems Biology (CSSB), Hamburg, Germany.
| | - Patrick Behrendt
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany.
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
- German Center for Infection Research (DZIF), Braunschweig, Germany.
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13
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Frericks N, Klöhn M, Lange F, Pottkämper L, Carpentier A, Steinmann E. Host-targeting antivirals for chronic viral infections of the liver. Antiviral Res 2025; 234:106062. [PMID: 39716667 DOI: 10.1016/j.antiviral.2024.106062] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.
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Affiliation(s)
- Nicola Frericks
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Frauke Lange
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Lilli Pottkämper
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Arnaud Carpentier
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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14
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Zhang F, Xu LD, Wu S, Wang B, Xu P, Huang YW. Deciphering the hepatitis E virus ORF1: Functional domains, protein processing, and patient-derived mutations. Virology 2025; 603:110350. [PMID: 39675187 DOI: 10.1016/j.virol.2024.110350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/25/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024]
Abstract
Hepatitis E virus (HEV) is a major cause of acute and chronic hepatitis in humans. The HEV open reading frames (ORF1) encodes a large non-structural protein essential for viral replication, which contains several functional domains, including helicase and RNA-dependent RNA polymerase. A confusing aspect is that, while RNA viruses typically encode large polyproteins that rely on their enzymatic activity for processing into functional units, the processing of the ORF1 protein and the mechanisms involved remain unclear. The ORF1 plays a pivotal role in the viral life cycle, thus mutations in this region, especially those occurring under environmental pressures such as during antiviral drug treatment, could significantly affect viral replication and survival. Here, we summarize the recent advances in the functional domains, processing, and mutations of ORF1. Gaining a deeper understanding of HEV biology, particularly focusing on ORF1, could facilitate the development of new strategies to control HEV infections.
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Affiliation(s)
- Fei Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Ling-Dong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Laboratory Animal Center, Zhejiang University, Hangzhou, 310058, China
| | - Shiying Wu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, 310018, China
| | - Bin Wang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China
| | - Pinglong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Yao-Wei Huang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China.
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15
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Gomes CTDO, Mariz CA, Batista AD, Morais CNLD, Araújo L, Sá Barreto AVM, Gomes-Gouvêa MS, Domingues AL, Lopes EP. Seroprevalence of Hepatitis E Virus Among Schistosomiasis mansoni Patients Residing in Endemic Zone in Brazil. Trop Med Infect Dis 2024; 9:310. [PMID: 39728837 DOI: 10.3390/tropicalmed9120310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/14/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024] Open
Abstract
The occurrence of hepatitis E virus (HEV) in patients with Schistosomiasis mansoni (SM) is still poorly understood in Brazil. The objective of this study was to estimate the seroprevalence of anti-HEV IgG in patients with SM and its association with the periportal fibrosis (PPF), assessed by serum markers and ultrasound criteria. This cross-sectional study was carried out in an endemic area in Pernambuco, Brazil, with schistosomal patients who underwent coproscopic survey. Anti-HEV antibody IgG were evaluated by using ELISA (Euroimmun®, Lübeck, Germmany). In positive cases, HEV-RNA was tested by using real-time PCR. Among the 286 patients (60.8% women; 56% 18-44 years), 116 (40.6%) had advanced PPF (Niamey pattern D/E/F). Anti-HEV IgG was positive in 15 (5.24%), and all were HEV-RNA negative. Anti-HEV IgG was more frequent in patients with an advanced PPF (D/E/F) pattern (p = 0.034) and those with the largest spleen diameter (p = 0.039). In this study, the occurrence of anti-HEV IgG in patients with SM was higher than described in the same region and more frequent among patients with evidence of advanced liver fibrosis.
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Affiliation(s)
| | - Carolline Araujo Mariz
- Department of Parasitology, Aggeu Magalhães Institute, Fiocruz, Recife 50740-465, PE, Brazil
- Faculdade de Medicina de Olinda (FMO), Olinda 53030-030, PE, Brazil
| | - Andrea Dória Batista
- Gastroenterology Division, Hospital das Clínicas/EBSERH, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
- Department of Internal Medicine, Center of Medical Sciences, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
| | | | - Lílian Araújo
- Gastroenterology Division, Hospital das Clínicas/EBSERH, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
| | | | - Michele Soares Gomes-Gouvêa
- Laboratory of Gastroenterology and Tropical Hepatology (LIM-07), Institute of Tropical Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, SP, Brazil
| | - Ana Lúcia Domingues
- Postgraduate Program in Tropical Medicine, Center of Medical Sciences, Universidade Federal de Pernambuco (UFPE), Recife 50670-420, PE, Brazil
- Gastroenterology Division, Hospital das Clínicas/EBSERH, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
| | - Edmundo Pessoa Lopes
- Postgraduate Program in Tropical Medicine, Center of Medical Sciences, Universidade Federal de Pernambuco (UFPE), Recife 50670-420, PE, Brazil
- Gastroenterology Division, Hospital das Clínicas/EBSERH, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
- Department of Internal Medicine, Center of Medical Sciences, Universidade Federal de Pernambuco (UFPE), Recife 50670-901, PE, Brazil
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16
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Nagashima S, Primadharsini PP, Takahashi M, Nishiyama T, Murata K, Okamoto H. Role of Rab13, Protein Kinase A, and Zonula Occludens-1 in Hepatitis E Virus Entry and Cell-to-Cell Spread: Comparative Analysis of Quasi-Enveloped and Non-Enveloped Forms. Pathogens 2024; 13:1130. [PMID: 39770389 PMCID: PMC11678111 DOI: 10.3390/pathogens13121130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Hepatitis E virus (HEV) exists in two distinct forms: a non-enveloped form (neHEV), which is present in feces and bile, and a quasi-enveloped form (eHEV), found in circulating blood and culture supernatants. This study aimed to elucidate the roles of Ras-associated binding 13 (Rab13) and protein kinase A (PKA) in the entry mechanisms of both eHEV and neHEV, utilizing small interfering RNA (siRNA) and chemical inhibitors. The results demonstrated that the entry of both viral forms is dependent on Rab13 and PKA. Further investigation into the involvement of tight junction (TJ) proteins revealed that the targeted knockdown of zonula occludens-1 (ZO-1) significantly impaired the entry of both eHEV and neHEV. In addition, in ZO-1 knockout (KO) cells inoculated with either viral form, HEV RNA levels in culture supernatants did not increase, even up to 16 days post-inoculation. Notably, the absence of ZO-1 did not affect the adsorption efficiency of eHEV or neHEV, nor did it influence HEV RNA replication. In cell-to-cell spread assays, ZO-1 KO cells inoculated with eHEV showed a lack of expression of HEV ORF2 and ORF3 proteins. In contrast, neHEV-infected ZO-1 KO cells showed markedly reduced ORF2 and ORF3 protein expression within virus-infected foci, compared to non-targeting knockout (NC KO) cells. These findings underscore the crucial role of ZO-1 in facilitating eHEV entry and mediating the cell-to-cell spread of neHEV in infected cells.
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Affiliation(s)
- Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan; (P.P.P.); (M.T.); (T.N.); (K.M.)
| | | | | | | | | | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan; (P.P.P.); (M.T.); (T.N.); (K.M.)
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17
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Zhu K, Liao M, Chen L, Lu J, Huang X, Zhuang C, Su Y, Huang S, Wu T, Zhang J, Xia N. Persistence of hepatitis E vaccine-induced antibody response across different dosage schedules and baseline serostatus. NPJ Vaccines 2024; 9:245. [PMID: 39702395 DOI: 10.1038/s41541-024-01041-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/30/2024] [Indexed: 12/21/2024] Open
Abstract
Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide. The efficacy and safety of the HEV239 vaccine have been validated, with protection lasting at least 10 years. This study extended the phase 3 trial of HEV239 (NCT01014845), presenting data on the durability of the anti-HEV IgG response elicited by one or two doses in the participants with different baseline serostatus. Over half of baseline seronegative individuals retained detectable antibodies at month 91 after two doses, with geometric mean concentration levels above the detection limit at month 67 (no available data for month 91). Seropositive individuals exhibited more prolonged and higher anti-HEV IgG response. After a single dose, individuals with pre-existing immunity achieved high and sustained antibody levels for over 103 months, comparable to the two-dose regimen. Both single-dose and two-dose HEV239 regimens demonstrated notable immunogenicity and persistence, potentially offering substantial protective benefits.
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Grants
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 2023YFC2307602 National Key Research and Development Program of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 81991491 National Natural Science Foundation of China,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220006 Fundamental Research Funds for the Central Universities,China
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
- 20720220005 Fundamental Research Funds for the Central Universities,China,
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Affiliation(s)
- Kongxin Zhu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Mengjun Liao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Lu Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Jiaoxi Lu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Xingcheng Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Chunlan Zhuang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China.
| | - Yingying Su
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Shoujie Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Ting Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, China
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18
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Kang S, Chung E, Hong C, Aziz AB, Kirkwood CD, Marks F. Raising the case of hepatitis E: Report from the 2nd international HEV symposium. Vaccine 2024; 42:126398. [PMID: 39357463 DOI: 10.1016/j.vaccine.2024.126398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/02/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
The 2nd International Hepatitis E Virus Symposium was held on April 28 and 29, 2023, in London, UK. The conference was hosted by the International Vaccine Institute and brought together key clinicians, researchers, and private and public stakeholders for a dedicated forum on hepatitis E virus (HEV). The scientific program spanned multiple facets of HEV, from updates on clinical research and diagnostic advances to vaccine development. The conference highlighted presentations on several critical HEV vaccine studies that will greatly impact the field, including the largest effectiveness study of Hecolin vaccine outside of China and the first reactive mass-vaccination campaign in South Sudan. This report summarizes information shared at the convening and offers perspectives on the steps forward for hepatitis E.
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Affiliation(s)
- Sophie Kang
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea.
| | - Eun Chung
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Chloe Hong
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Asma Binte Aziz
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Carl D Kirkwood
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Florian Marks
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany; Madagascar Institute for Vaccine Research, University of Antananarivo, Antananarivo, Madagascar
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19
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Shun EHK, Situ J, Tsoi JYH, Wu S, Cai J, Lo KHY, Chew NFS, Li Z, Poon RWS, Teng JLL, Cheng VCC, Yuen KY, Sridhar S. Rat hepatitis E virus (Rocahepevirus ratti) exposure in cats and dogs, Hong Kong. Emerg Microbes Infect 2024; 13:2337671. [PMID: 38551320 PMCID: PMC11018080 DOI: 10.1080/22221751.2024.2337671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/27/2024] [Indexed: 04/06/2024]
Abstract
Hepatitis E virus (HEV) variants infecting humans belong to two species: Paslahepevirus balayani (bHEV) and Rocahepevirus ratti (rat hepatitis E virus; rHEV). R. ratti is a ubiquitous rodent pathogen that has recently been recognized to cause hepatitis in humans. Transmission routes of rHEV from rats to humans are currently unknown. In this study, we examined rHEV exposure in cats and dogs to determine if they are potential reservoirs of this emerging human pathogen. Virus-like particle-based IgG enzymatic immunoassays (EIAs) capable of differentiating rHEV & bHEV antibody profiles and rHEV-specific real-time RT-PCR assays were used for this purpose. The EIAs could detect bHEV and rHEV patient-derived IgG spiked in dog and cat sera. Sera from 751 companion dogs and 130 companion cats in Hong Kong were tested with these IgG enzymatic immunoassays (EIAs). Overall, 13/751 (1.7%) dogs and 5/130 (3.8%) cats were sero-reactive to HEV. 9/751 (1.2%) dogs and 2/130 (1.5%) cats tested positive for rHEV IgG, which was further confirmed by rHEV immunoblots. Most rHEV-seropositive animals were from areas in or adjacent to districts reporting human rHEV infection. Neither 881 companion animals nor 652 stray animals carried rHEV RNA in serum or rectal swabs. Therefore, we could not confirm a role for cats and dogs in transmitting rHEV to humans. Further work is required to understand the reasons for low-level seropositivity in these animals.
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Affiliation(s)
- Estie Hon-Kiu Shun
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Jianwen Situ
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - James Yiu-Hung Tsoi
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Shusheng Wu
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Jianpiao Cai
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Kelvin Hon-Yin Lo
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Nicholas Foo-Siong Chew
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Zhiyu Li
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Rosana Wing-Shan Poon
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Jade Lee-Lee Teng
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Vincent Chi-Chung Cheng
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Kwok-Yung Yuen
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
- Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong, People’s Republic of China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, People’s Republic of China
- Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, People’s Republic of China
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20
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Weiss N, Pflugrad H, Kandiah P. Altered Mental Status in the Solid-Organ Transplant Recipient. Semin Neurol 2024; 44:670-694. [PMID: 39181120 DOI: 10.1055/s-0044-1789004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Patients undergoing solid-organ transplantation (SOT) face a tumultuous journey. Prior to transplant, their medical course is characterized by organ dysfunction, diminished quality of life, and reliance on organ support, all of which are endured in hopes of reaching the haven of organ transplantation. Peritransplant altered mental status may indicate neurologic insults acquired during transplant and may have long-lasting consequences. Even years after transplant, these patients are at heightened risk for neurologic dysfunction from a myriad of metabolic, toxic, and infectious causes. This review provides a comprehensive examination of causes, diagnostic approaches, neuroimaging findings, and management strategies for altered mental status in SOT recipients. Given their complexity and the numerous etiologies for neurologic dysfunction, liver transplant patients are a chief focus in this review; however, we also review lesser-known contributors to neurological injury across various transplant types. From hepatic encephalopathy to cerebral edema, seizures, and infections, this review highlights the importance of recognizing and managing pre- and posttransplant neurological complications to optimize patient outcomes.
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Affiliation(s)
- Nicolas Weiss
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Neurological ICU, Paris, France
| | - Henning Pflugrad
- Department of Neurology, Agaplesion Ev. Klinikum Schaumburg, Obernkirchen, Germany
| | - Prem Kandiah
- Department of Neurology, Emory University Hospital, Atlanta, Georgia
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21
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Kao CM, Rostad CA, Nolan LE, Peters E, Kleinhenz J, Sherman JD, Tippett A, Shih JWK, Yildirim I, Agbakoba V, Beresnev T, Ballou C, Kamidani S, Karmali V, Natrajan M, Scherer EM, Rouphael N, Anderson EJ. A Phase 1, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Safety and Immunogenicity of HEV-239 (Hecolin) Vaccine in Healthy US Adults. J Infect Dis 2024; 230:1093-1101. [PMID: 38536442 PMCID: PMC11565884 DOI: 10.1093/infdis/jiae148] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality. METHODS We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine to placebo) trial of 30 µg HEV-239 (Hecolin, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM). RESULTS Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at 1 month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked 1 month following the second dose (geometric mean concentration [GMC], 6.16; 95% confidence interval [CI], 4.40-8.63), was boosted with the third dose (GMC, 11.50; 95% CI, 7.90-16.75) and persisted through 6 months. CONCLUSIONS HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults. CLINICAL TRIALS REGISTRATION NCT03827395.
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Affiliation(s)
- Carol M Kao
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Christina A Rostad
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Lauren E Nolan
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Etza Peters
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Jennifer Kleinhenz
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Jacob D Sherman
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Ashley Tippett
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | | | - Inci Yildirim
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Vivien Agbakoba
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
| | - Tatiana Beresnev
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
| | | | - Satoshi Kamidani
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Vinit Karmali
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Muktha Natrajan
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Erin M Scherer
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Nadine Rouphael
- Hope Clinic, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Evan J Anderson
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
- Center for Childhood Infections and Vaccines, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
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22
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Wang B, Subramaniam S, Tian D, Mahsoub HM, Heffron CL, Meng XJ. Phosphorylation of Ser711 residue in the hypervariable region of zoonotic genotype 3 hepatitis E virus is important for virus replication. mBio 2024; 15:e0263524. [PMID: 39377575 PMCID: PMC11559016 DOI: 10.1128/mbio.02635-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 10/09/2024] Open
Abstract
Hepatitis E virus (HEV) is distinct from other hepatotropic viruses because it is zoonotic. HEV-1 and HEV-2 exclusively infect humans, whereas HEV-3 and HEV-4 are zoonotic. However, the viral and/or host factors responsible for cross-species HEV transmission remain elusive. The hypervariable region (HVR) in HEV is extremely heterogenetic and is implicated in HEV adaptation. Here, we investigated the potential role of Serine phosphorylation in the HVR in HEV replication. We first analyzed HVR sequences across different HEV genotypes and identified a unique region at the N-terminus of the HVR, which is variable in the human-exclusive HEV genotypes but relatively conserved in zoonotic HEV genotypes. Using predictive tools, we identified four potential phosphorylation sites that are highly conserved in zoonotic HEV-3 and HEV-4 genomes but absent in human-exclusive HEV-1 strains. To explore the functional significance of these putative phosphorylation sites, we introduced mutations into the HEV-3 infectious clone and indicator replicon, replacing each Serine residue individually with alanine or aspartic acid, and assessed the impact of these substitutions on HEV-3 replication. We found that the phospho-blatant S711A mutant significantly reduced virus replication, whereas the phospho-mimetic S711D mutant modestly reduced virus replication. Conversely, mutations in the other three Serine residues did not significantly affect HEV-3 replication. Furthermore, we demonstrated that Ser711 phosphorylation did not alter host cell tropism of zoonotic HEV-3. In conclusion, our results showed that potential phosphorylation of the Ser711 residue significantly affects HEV-3 replication in vitro, providing new insights into the potential mechanisms of zoonotic HEV transmission.IMPORTANCEHEV is an important zoonotic pathogen, causing both acute and chronic hepatitis E and extrahepatic manifestation of diseases, such as neurological sequelae. The zoonotic HEV-3 is linked to chronic infection and neurological diseases. The specific viral and/or host factors facilitating cross-species HEV infection are unknown. The intrinsically disordered HVR in ORF1 is crucial for viral fitness and adaptation, both in vitro and in vivo. We hypothesized that phosphorylation of Serine residues in the HVR of zoonotic HEV by unknown host cellular kinases is associated with cross-species HEV transmission. In this study, we identified a conserved region within the HVR of zoonotic HEV strains but absent in the human-exclusive HEV-1 and HEV-2. We elucidated the important role of phosphorylation at the Ser711 residue in zoonotic HEV-3 replication, without altering the host cell tropism. These findings contribute to our understanding the mechanisms of cross-species HEV transmission.
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Affiliation(s)
- Bo Wang
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Sakthivel Subramaniam
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Debin Tian
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Hassan M. Mahsoub
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - C. Lynn Heffron
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Xiang-Jin Meng
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
- Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
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23
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Barreiros AP, Böhler K, Mönch K, Fischer-Fröhlich CL, Rahmel A. Perspectives on donor-derived infections from Germany. Transpl Infect Dis 2024; 26 Suppl 1:e14372. [PMID: 39311724 DOI: 10.1111/tid.14372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/19/2024] [Accepted: 08/25/2024] [Indexed: 11/21/2024]
Abstract
AIM Often, organ transplantation is the only option to improve the life expectancy and quality of life of patients with terminal organ failure. Despite improved donor and organ assessment, a residual risk remains for transmitting infection, tumor, or other disease from the donor to recipients. Analysis, reporting, and managing of donor-derived diseases through a vigilance and surveillance system (V&S) is mandatory in many countries. We report on suspected and proven/probable donor-derived infections (DDI) in Germany over a period of 8 years (2016-2023). METHODS All incoming serious-adverse-event and serious-adverse-reaction (SAE/SAR) reports from 01.01.2016 to 31.12.2023 were evaluated for suspected DDI. Analysis of imputability followed the definition of the US Disease Transmission Advisory Committee (DTAC). Only probable and proven cases according to DTAC classification were defined as DDI. RESULTS During the study period, 9771 donors in Germany donated post-mortem organs to 27 919 recipients. In that period 612 SAE/SAR cases were reported, 377 (62%) involved infections. 41 cases were proven/probable DDI affecting 58 recipients (seven recipients died, 12%). Suspected infections were bacterial (182/377, 48%), fungal (135/377, 36%), viral (55/377, 15%), and parasitic (5/377, 1%). In case of bacterial DDI, no recipient died, but organ loss occurred in six recipients. In case of fungal or viral DDI, 19% (3/16) and 21% (3/14) of the recipients died, respectively. CONCLUSIONS DDI are rare in solid organ transplantation (58/27 919, 0.21%), but when they occur, they are associated with high morbidity and mortality in affected recipients. Careful and detailed donor evaluation and a reliable V&S help improve recipient safety.
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Affiliation(s)
- Ana Paula Barreiros
- Geschäftsführende Ärztin, Deutsche Stiftung Organtransplantation, Region Mitte, Organisationszentrale, Mainz, Germany
| | - Klaus Böhler
- Deutsche Stiftung Organtransplantation, Hauptverwaltung, Frankfurt, Germany
| | - Kerstin Mönch
- Verbundprojekt KITTU, Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsmedizin Mainz, Mainz, Germany
| | | | - Axel Rahmel
- Deutsche Stiftung Organtransplantation, Hauptverwaltung, Frankfurt, Germany
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24
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Gong G, Xin J, Lou Y, Qiong D, Dawa Z, Gesang Z, Suolang S. Cell Culture of a Swine Genotype 4 Hepatitis E Virus Strain. J Med Virol 2024; 96:e70031. [PMID: 39530175 DOI: 10.1002/jmv.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/12/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
HEV infection has become a global health concern. The study of HEV pathogenicity has been hindered by the lack of a suitable in vitro culture system. In the present research, we systematic demonstration of efficient replication of swine GT4 HEV in A549 cells, Huh-7 cells, and HepG2/C3A cell lines. The results of the immunofluorescence assay and immunofluorescence confocal assay showed that swine GT4 HEV is efficiently replicated in three cell lines at 72 h postinoculation. Meanwhile, we also detected the virus titer quantified were increased at 2-, 6,- and 11-days postinoculation. Moreover, we successfully observed HEV virus particles in the cell suspension at 6 days postinoculation. This finding holds significance for advancing in vitro HEV studies.
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Affiliation(s)
- Ga Gong
- Animal Science College, Xizang Agriculture and Animal Husbandry University, Nyingchi, China
| | - Jiaojiao Xin
- Animal Science College, Xizang Agriculture and Animal Husbandry University, Nyingchi, China
| | - Yongzhi Lou
- Animal Science College, Xizang Agriculture and Animal Husbandry University, Nyingchi, China
| | - Da Qiong
- Animal Science College, Xizang Agriculture and Animal Husbandry University, Nyingchi, China
| | | | - Zhuoma Gesang
- Animal Disease Prevention and Control Center of Xizang Autonomous Region, Lhasa, China
| | - Sizhu Suolang
- Animal Science College, Xizang Agriculture and Animal Husbandry University, Nyingchi, China
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25
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Serricchio M, Gowland P, Widmer N, Stolz M, Niederhauser C. HEV in Blood Donors in Switzerland: The Route to Safe Blood Products. Pathogens 2024; 13:911. [PMID: 39452782 PMCID: PMC11510004 DOI: 10.3390/pathogens13100911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/08/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
The hepatitis E virus (HEV) is an emerging infectious disease with zoonotic potential, causing acute hepatitis in humans. Infections in healthy individuals are often acute, self-limiting and asymptomatic, thus leading to the underdiagnosis of HEV infections. Asymptomatic HEV infections pose a problem for blood transfusion safety by increasing the risk for transfusion-transmitted HEV infections. Here, we describe the journey from determining the HEV seroprevalence among blood donors to the implementation of routine HEV RNA testing of all blood products in Switzerland in 2018 and summarise the HEV cases detected since. In total, 290 HEV-positive blood donations were detected by mini-pool nucleic acid testing (NAT) in Switzerland in the period of October 2018-December 2023, equal to an incidence of 20.7 per 100,000 donations. Thanks to the implemented scheme, no transfusion-transmitted infections occurred in this period. Furthermore, blood donation monitoring has proven to be an effective means of detecting HEV outbreaks in the general population. HEV cases in Swiss blood donors are caused by two major genotypes, the Swiss-endemic subtypes 3h3 and 3c. Interestingly, 11 HEV cases (5%) were of genotype 3ra, a variant found in wild and farmed rabbits. Our results indicate that mini-pool NAT is an efficient method to reduce the risk of transfusion-transmitted HEV infections.
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Affiliation(s)
- Mauro Serricchio
- Interregional Blood Transfusion SRC, 3008 Bern, Switzerland; (M.S.); (P.G.); (M.S.)
| | - Peter Gowland
- Interregional Blood Transfusion SRC, 3008 Bern, Switzerland; (M.S.); (P.G.); (M.S.)
| | - Nadja Widmer
- Interregional Blood Transfusion SRC, 3008 Bern, Switzerland; (M.S.); (P.G.); (M.S.)
| | - Martin Stolz
- Interregional Blood Transfusion SRC, 3008 Bern, Switzerland; (M.S.); (P.G.); (M.S.)
| | - Christoph Niederhauser
- Interregional Blood Transfusion SRC, 3008 Bern, Switzerland; (M.S.); (P.G.); (M.S.)
- Institute for Infectious Diseases, University of Bern, 3012 Bern, Switzerland
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26
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Leblond AL, Helmchen B, Ankavay M, Lenggenhager D, Jetzer J, Helmchen F, Yurtsever H, Parrotta R, Healy ME, Pöschel A, Markkanen E, Semmo N, Ferrié M, Cocquerel L, Seeger H, Hopfer H, Müllhaupt B, Gouttenoire J, Moradpour D, Gaspert A, Weber A. HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status. Nat Commun 2024; 15:8849. [PMID: 39397005 PMCID: PMC11471813 DOI: 10.1038/s41467-024-53072-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 09/27/2024] [Indexed: 10/15/2024] Open
Abstract
Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications.
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Affiliation(s)
- Anne-Laure Leblond
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Birgit Helmchen
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Maliki Ankavay
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Jasna Jetzer
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Fritjof Helmchen
- Brain Research Institute, University of Zurich, Zurich, Switzerland
| | | | - Rossella Parrotta
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Marc E Healy
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Amiskwia Pöschel
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse Faculty, Zürich, Switzerland
| | - Enni Markkanen
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse Faculty, Zürich, Switzerland
| | - Nasser Semmo
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Martin Ferrié
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Laurence Cocquerel
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Harald Seeger
- Clinic of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Helmut Hopfer
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jérôme Gouttenoire
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Ariana Gaspert
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland.
- Institute of Molecular Cancer Research (IMCR), University of Zurich (UZH), Zurich, Switzerland.
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27
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Liu C, Tang D, Shi J, Chen G, Gong L. Hepatitis E virus and SARS-CoV-2 co-infection in an immunocompromised patient: A case report. Diagn Microbiol Infect Dis 2024; 110:116471. [PMID: 39079189 DOI: 10.1016/j.diagmicrobio.2024.116471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 07/13/2024] [Accepted: 07/26/2024] [Indexed: 08/24/2024]
Abstract
Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Since the coronavirus disease 2019 (COVID-19) pandemic, immunocompromised individuals face an increased risk of HEV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection, posing a threat of liver failure and prolonged illness. A 69-year-old male, with a history of chronic lymphocytic leukemia, was co-infected with HEV and SARS-CoV-2. Given the progressive decline in liver function post-admission, steroid therapy was initiated, which led to treatment-related complications. Additionally, the patient experienced an aggravation of COVID-19 symptoms due to persistent SARS-CoV-2 infection, effectively managed through a combination of antiviral medications and corticosteroids. This case describes the intricate clinical trajectory and therapeutic approach for managing HEV and SARS-CoV-2 co-infection, underscoring the potential efficacy of short-term corticosteroid intervention alongside comprehensive antiviral treatment.
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Affiliation(s)
- Chun Liu
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Dong Tang
- Department of Medical Imaging (Radiology), The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Junping Shi
- Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Gongying Chen
- Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Ling Gong
- Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China.
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28
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Brüggemann Y, Klöhn M, Wedemeyer H, Steinmann E. Hepatitis E virus: from innate sensing to adaptive immune responses. Nat Rev Gastroenterol Hepatol 2024; 21:710-725. [PMID: 39039260 DOI: 10.1038/s41575-024-00950-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/24/2024]
Abstract
Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.
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Affiliation(s)
- Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Sites Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
- German Center for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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29
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He P, Li J, Wang C, Zhang J, Jiang Y, Liu H, Zhao Y, Li Z, Gao Y, Wang Y. Incidence and risk factors of de novo hepatitis E virus infection after receiving liver transplantation. J Med Virol 2024; 96:e29939. [PMID: 39360633 DOI: 10.1002/jmv.29939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
Organ transplant recipients with hepatitis E virus (HEV) infection bears high risk to develop chronic hepatitis, which is generally associated with immunosuppressive therapies. This study aimed to identify the incidence and predictors of de novo HEV infection in patients after receiving transplantation. We performed a large retrospective study to investigate the prevalence of anti-HEV at baseline, incidence of de novo HEV infection after transplantation, and the risk factors of HEV infection among patients with liver transplant in China. A total of 407 liver transplant recipients were examined for the presence of anti-HEV immunoglobulin G, IgM antibodies, and HEV RNA in serum. Basal indexes in individuals with evidence of post-transplant HEV infection were compared with those without evidence of that, and risk factors associated with HEV infection were assessed. The prevalence of anti-HEV at pretransplant in liver transplant recipients was 25.8% (105/407). Serum-negative conversion occurred in 34 (32.38%) of 105 liver transplant patients. Sixty-five out of 302 patients had de novo HEV infection after transplantation, with a cumulative incidence of 42.74% during follow-up. After transplantation, HEV infection was associated with liver failure (p = 0.012), hypoproteinemia (p = 0.030) and higher level of r-glutamyl transferase (GGT) (p = 0.022) before transplantation. Graft rejection (OR = 0.075; p = 0.045) was negatively associated with serum-negative conversion in patients who had positive anti-HEV antibody before transplantation. The incidence of de novo HEV infection after transplantation were higher in China. Liver failure, hypoproteinemia, and GGT elevation may be associated with HEV infection after liver transplantation. This study suggests that prevention and control of HEV infection after liver transplantation should be paid attention in patients bearing these risk factors.
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Affiliation(s)
- Ping He
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jialei Li
- Medical School of Nanjing University, Nanjing, China
| | - Chen Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Jiayue Zhang
- School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, China
| | - Yiyun Jiang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongyang Liu
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yao Zhao
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhiwei Li
- Department of Hepato-Biliary Surgery, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Yinjie Gao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yijin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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30
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Yadav KK, Kenney SP. Hepatitis E virus immunosuppressed animal models. BMC Infect Dis 2024; 24:965. [PMID: 39266958 PMCID: PMC11395946 DOI: 10.1186/s12879-024-09870-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.
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Affiliation(s)
- Kush Kumar Yadav
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA
| | - Scott P Kenney
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA.
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA.
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31
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Muñoz-Chimeno M, Díaz-Sánchez N, Morago L, Rodríguez-Paredes V, Barturen S, Rodríguez-Recio Á, García-Lugo MA, Zamora MI, Mateo M, Sánchez-Martínez M, Avellón A. Performance Comparison of Four Hepatitis E Antibodies Detection Methods. Microorganisms 2024; 12:1875. [PMID: 39338549 PMCID: PMC11434459 DOI: 10.3390/microorganisms12091875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/28/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
HEV antibody detection constitutes the main screening test for HEV infection. The aim of this study is to compare the sensitivity and specificity of four techniques: LIAISON® MUREX DiaSorin anti-HEV IgG and anti-HEV IgM assays, Hepatitis E VIRCLIA® IgM and IgG monotests, WANTAI HEV-IgM and IgG ELISA and VIDAS® anti-HEV IgM and IgG tests in five panels of samples configurated according to the immunoblot (RecomLine, Mikrogen, Neuss, Germany). Anti-HEV IgM sensitivity in the acute phase was 100% in all techniques, while sensitivity, including the immediate convalescence phase, was 96.74% for LIAISON®, 83.14% for VIRCLIA®, 84.78% for WANTAI and 88.04% for VIDAS®. Anti-HEV IgM specificity was 100% for both LIAISON® and VIRCLIA®. Anti-HEV IgM WANTAI agreed with VIRCLIA® with a good Kappa coefficient (κ = 0.71). Anti-HEV IgG post-infection sensitivity was 100% for LIAISON®, VIDAS® and VIRCLIA® and 99% for WANTAI. Anti-HEV IgG specificity reached 97.17% for LIAISON and 88.68% for VIRCLIA®. Our results demonstrated a better capacity of LIAISON® MUREX anti-HEV IgM than that of competitors for detecting acute infections as well as accurate anti-HEV IgG results and in how to resolve them.
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Affiliation(s)
- Milagros Muñoz-Chimeno
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Nazaret Díaz-Sánchez
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Lucía Morago
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | | | - Silvia Barturen
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Álvaro Rodríguez-Recio
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | | | - Maria Isabel Zamora
- Servicio de Microbiología, Hospital Central de la Defensa, 28047 Madrid, Spain
| | - María Mateo
- Servicio de Microbiología, Hospital Central de la Defensa, 28047 Madrid, Spain
| | | | - Ana Avellón
- Hepatitis Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
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32
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Thornton CS, Waddell BJ, Congly SE, Svishchuk J, Somayaji R, Fatovich L, Isaac D, Doucette K, Fonseca K, Drews SJ, Borlang J, Osiowy C, Parkins MD. Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients. Gut 2024; 73:1702-1711. [PMID: 38621922 PMCID: PMC11420761 DOI: 10.1136/gutjnl-2023-330602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 04/02/2024] [Indexed: 04/17/2024]
Abstract
OBJECTIVES In high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers. DESIGN All pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV. RESULTS HEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases. CONCLUSION PwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.
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Affiliation(s)
- Christina S Thornton
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Barbara J Waddell
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Stephen E Congly
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Julianna Svishchuk
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Ranjani Somayaji
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Linda Fatovich
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Debra Isaac
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Karen Doucette
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Kevin Fonseca
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Steven J Drews
- Canadian Blood Services, Edmonton, Alberta, Canada
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Jamie Borlang
- Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Carla Osiowy
- Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Michael D Parkins
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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33
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Quirino A, Marascio N, Branda F, Ciccozzi A, Romano C, Locci C, Azzena I, Pascale N, Pavia G, Matera G, Casu M, Sanna D, Giovanetti M, Ceccarelli G, Alaimo di Loro P, Ciccozzi M, Scarpa F, Maruotti A. Viral Hepatitis: Host Immune Interaction, Pathogenesis and New Therapeutic Strategies. Pathogens 2024; 13:766. [PMID: 39338957 PMCID: PMC11435051 DOI: 10.3390/pathogens13090766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.
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Affiliation(s)
- Angela Quirino
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Nadia Marascio
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Francesco Branda
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Alessandra Ciccozzi
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Chiara Romano
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Chiara Locci
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Ilenia Azzena
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Noemi Pascale
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
- Department of Chemical Physical Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
| | - Grazia Pavia
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Giovanni Matera
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro “Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (A.Q.); (N.M.); (G.P.); (G.M.)
| | - Marco Casu
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Daria Sanna
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Marta Giovanetti
- Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, MG, Brazil
- Climate Amplified Diseases and Epidemics (CLIMADE), Brasilia 70070-130, GO, Brazil
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | | | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Fabio Scarpa
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.); (F.S.)
| | - Antonello Maruotti
- Department GEPLI, Libera Università Maria Ss Assunta, 00193 Rome, Italy;
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Ziersch M, Harms D, Neumair L, Kurreck A, Johne R, Bock CT, Kurreck J. Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication. Viruses 2024; 16:1378. [PMID: 39339854 PMCID: PMC11435946 DOI: 10.3390/v16091378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/19/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies.
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Affiliation(s)
- Mathias Ziersch
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Dominik Harms
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Lena Neumair
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Anke Kurreck
- Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
- BioNukleo GmbH, Ackerstrasse 76, 13355 Berlin, Germany
| | - Reimar Johne
- Department of Biological Safety, German Federal Institute for Risk Assessment, 12277 Berlin, Germany
| | - C-Thomas Bock
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Jens Kurreck
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
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36
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Gu T, Zheng CY, Deng YQ, Yang XF, Bao WM, Tang YM. Systematic Evaluation of Guidelines for the Diagnosis and Treatment of Hepatitis E Virus Infection. J Clin Transl Hepatol 2024; 12:739-749. [PMID: 39130619 PMCID: PMC11310757 DOI: 10.14218/jcth.2023.00508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 05/14/2024] [Accepted: 05/16/2024] [Indexed: 08/13/2024] Open
Abstract
Background and Aims The hepatitis E virus (HEV) is a zoonotic disease, and infection with HEV in humans primarily causes acute infections and can progress to chronic manifestation in immunocompromised individuals. Over the past decade, guidelines for diagnosing and treating HEV infection have been developed. This study aimed to systematically assess the quality of current guidelines for diagnosing and treating HEV infection, and we analyzed the differences in guideline quality and primary recommendations and explored possible reasons for these differences. Methods Guidelines published between 2013 and 2022 were searched, and studies were identified using selection criteria. The study assessed the quality of the included guidelines using the Appraisal of Guidelines for Research and Evaluation tool, extracted the primary recommendations in the guidelines, determined the highest level of evidence supporting the recommendations, and reclassified the evidence using the Oxford Centre for Evidence-Based Medicine grading system. Results Seven guidelines were included in the final analysis. The quality of the guidelines varied widely. The discrepancies may have been caused by the lack of external experts, the failure to consider influencing factors in guideline application, and the lack of consideration of the public's opinion. Analysis of the heterogeneity in primary recommendations revealed differences in algorithms for managing chronic HEV infection, the dosage of ribavirin, and a low level of evidence supporting the primary recommendations. Conclusions Guideline quality and primary recommendations vary considerably. Refinement by guideline developers and researchers would facilitate updating and applying guidelines for diagnosing and treating HEV infection.
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Affiliation(s)
- Ting Gu
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, Yunnan, China
| | - Cai-Ying Zheng
- Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yan-Qin Deng
- Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xiao-Feng Yang
- Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wei-Min Bao
- Department of Colorectal Surgery, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Ying-Mei Tang
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, Yunnan, China
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Letafati A, Taghiabadi Z, Roushanzamir M, Memarpour B, Seyedi S, Farahani AV, Norouzi M, Karamian S, Zebardast A, Mehrabinia M, Ardekani OS, Fallah T, Khazry F, Daneshvar SF, Norouzi M. From discovery to treatment: tracing the path of hepatitis E virus. Virol J 2024; 21:194. [PMID: 39180020 PMCID: PMC11342613 DOI: 10.1186/s12985-024-02470-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.
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Affiliation(s)
- Arash Letafati
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Zahra Taghiabadi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mahshid Roushanzamir
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Department of Pharmacological and Biomolecular Science, University of Milan, Milan, Italy
| | - Bahar Memarpour
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Saba Seyedi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | | | - Masoomeh Norouzi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Saeideh Karamian
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Arghavan Zebardast
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Marzieh Mehrabinia
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Omid Salahi Ardekani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Tina Fallah
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Khazry
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Samin Fathi Daneshvar
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Norouzi
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
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Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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He Q, Liu T, Yang X, Yuan D, Lu Q, Li Y, Zhang H, Liu X, Xia C, Sridhar S, Tian L, Liu X, Meng L, Ning J, Lu F, Wang L, Yin X, Wang L. Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits. J Virol 2024; 98:e0084624. [PMID: 38899900 PMCID: PMC11264948 DOI: 10.1128/jvi.00846-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.
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Affiliation(s)
- Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xinyue Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Disen Yuan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qinghui Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuebao Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - He Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xing Liu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Changyou Xia
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lili Tian
- Miyun District Center for Disease Control and Prevention, Beijing, China
| | - Xiaofeng Liu
- Beijing Center for Disease Prevention and Control, Beijing, China
| | - Lulu Meng
- Beijing Center for Disease Prevention and Control, Beijing, China
| | - Jing Ning
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xin Yin
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Yadav KK, Boley PA, Lee CM, Khatiwada S, Jung K, Laocharoensuk T, Hofstetter J, Wood R, Hanson J, Kenney SP. Rat hepatitis E virus cross-species infection and transmission in pigs. PNAS NEXUS 2024; 3:pgae259. [PMID: 39035038 PMCID: PMC11259135 DOI: 10.1093/pnasnexus/pgae259] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 06/14/2024] [Indexed: 07/23/2024]
Abstract
Strains of Rocahepevirus ratti, an emerging hepatitis E virus (HEV), have recently been found to be infectious to humans. Rats are a primary reservoir of the virus; thus, it is referred to as "rat HEV". Rats are often found on swine farms in close contact with pigs. Our goal was to determine whether swine may serve as a transmission host for zoonotic rat HEV by characterizing an infectious cDNA clone of a zoonotic rat HEV, strain LCK-3110, in vitro and in vivo. RNA transcripts of LCK-3110 were constructed and assessed for their replicative capacity in cell culture and in gnotobiotic pigs. Fecal suspension from rat HEV-positive gnotobiotic pigs was inoculated into conventional pigs co-housed with naïve pigs. Our results demonstrated that capped RNA transcripts of LCK-3110 rat HEV replicated in vitro and successfully infected conventional pigs that transmit the virus to co-housed animals. The infectious clone of rat HEV may afford an opportunity to study the genetic mechanisms of rat HEV cross-species infection and tissue tropism.
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Affiliation(s)
- Kush Kumar Yadav
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA
| | - Patricia A Boley
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
| | - Carolyn M Lee
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA
| | - Saroj Khatiwada
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
| | - Kwonil Jung
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
| | - Thamonpan Laocharoensuk
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA
| | - Jake Hofstetter
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
| | - Ronna Wood
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
| | - Juliette Hanson
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA
| | - Scott P Kenney
- Department of Animal Sciences, Center for Food Animal Health, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA
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Bienz M, Renaud C, Liu JR, Wong P, Pelletier P. Hepatitis E Virus in the United States and Canada: Is It Time to Consider Blood Donation Screening? Transfus Med Rev 2024; 38:150835. [PMID: 39059853 DOI: 10.1016/j.tmrv.2024.150835] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 07/28/2024]
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the world and can lead to severe complications in immunocompromised individuals. HEV is primarily transmitted through eating pork, which has led to an increased in anti-HEV IgG seropositivity in the general population of Europe in particular. However, it can also be transmitted intravenously, such as through transfusions. The growing evidence of HEV contamination of blood products and documented cases of transmission have given rise to practice changes and blood product screening of HEV in many European countries. This review covers the abundant European literature and focuses on the most recent data pertaining to the prevalence of HEV RNA positivity and IgG seropositivity in the North American general population and in blood products from Canada and the United States. Currently, Health Canada and the Food and Drug Administration do not require testing of HEV in blood products. For this reason, awareness among blood product prescribers about the possibility of HEV transmission through blood products is crucial. However, we also demonstrate that the province of Quebec has a prevalence of anti-HEV and HEV RNA positivity similar to some European countries. In light of this, we believe that HEV RNA blood donation screening be reevaluated with the availability of more cost-effective assays.
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Affiliation(s)
- Marc Bienz
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Division of Hematology, Department of Medicine, McGill University, Montreal, Quebec, Canada.
| | - Christian Renaud
- Department of Microbiology, Infectious diseases, and Immunology, Université de Montréal, Montreal, Quebec, Canada; Medical Affairs and Innovation, Héma-Québec, Montreal, Quebec, Canada
| | - Jia Ru Liu
- Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Philip Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Patricia Pelletier
- Division of Hematology, Department of Medicine, McGill University, Montreal, Quebec, Canada
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Hartley C, Wasuwanich P, Van T, Karnsakul W. Hepatitis E Vaccines Updates. Vaccines (Basel) 2024; 12:722. [PMID: 39066361 PMCID: PMC11281573 DOI: 10.3390/vaccines12070722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
The development of a hepatitis E vaccine is imperative given its prevalence and the heightened risk it poses to specific populations. Hepatitis E virus infection, though often self-limiting, poses a significant threat to pregnant individuals and immunocompromised populations. This review delves into the historical trajectory of hepatitis E vaccine development and explores its potential impact on at-risk populations. Historically, efforts to formulate an effective vaccine against hepatitis E have been underway to mitigate the severity of the disease, particularly in regions where the infection is commonplace. As a self-limiting disease, the necessity of a vaccine becomes more pronounced when considering vulnerable demographics. Pregnant individuals face heightened complications, with potential adverse outcomes for both mother and child. Similarly, immunocompromised individuals experience prolonged and severe manifestations of the infection, necessitating targeted preventive measures. This review aims to provide a comprehensive overview of the milestones in hepatitis E vaccine development. By examining the historical progression, we aim to underscore the critical need for a vaccine to safeguard not only the general population but also those at elevated risk. The elucidation of the vaccine's journey will contribute valuable insights into its potential benefits, aiding in the formulation of informed public health strategies to combat hepatitis E effectively.
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Affiliation(s)
- Christopher Hartley
- The Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, MD 21287, USA
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Trung Van
- Department of Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Wikrom Karnsakul
- Pediatric Liver Center, The Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, MD 21287, USA;
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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Zhao W, Xia Y, Li T, Liu H, Zhong G, Chen D, Yu W, Li Y, Huang F. Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1365-1372. [PMID: 38877781 PMCID: PMC11532201 DOI: 10.3724/abbs.2024091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/20/2024] [Indexed: 06/16/2024] Open
Abstract
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.
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Affiliation(s)
- Wanqiu Zhao
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Yueping Xia
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Tengyuan Li
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Huichan Liu
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Guo Zhong
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Dongxue Chen
- Medical FacultyKunming University of Science and TechnologyKunming650500China
| | - Wenhai Yu
- Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeKunming650038China
| | - Yunlong Li
- Medical FacultyKunming University of Science and TechnologyKunming650500China
- Yunnan Provincial Key Laboratory of Clinical VirologyKunming650032China
| | - Fen Huang
- Medical FacultyKunming University of Science and TechnologyKunming650500China
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Paronetto O, Allioux C, Diméglio C, Lobjois L, Jeanne N, Ranger N, Boineau J, Pucelle M, Demmou S, Abravanel F, Chapuy-Regaud S, Izopet J, Lhomme S. Characterization of virus‒host recombinant variants of the hepatitis E virus. J Virol 2024; 98:e0029524. [PMID: 38712945 PMCID: PMC11237545 DOI: 10.1128/jvi.00295-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
Hepatitis E virus is a single-strand, positive-sense RNA virus that can lead to chronic infection in immunocompromised patients. Virus-host recombinant variants (VHRVs) have been described in such patients. These variants integrate part of human genes into the polyproline-rich region that could introduce new post-translational modifications (PTMs), such as ubiquitination. The aim of this study was to characterize the replication capacity of different VHRVs, namely, RNF19A, ZNF787, KIF1B, EEF1A1, RNA18, RPS17, and RPL6. We used a plasmid encoding the Kernow strain, in which the fragment encoding the S17 insertion was deleted (Kernow p6 delS17) or replaced by fragments encoding the different insertions. The HEV RNA concentrations in the supernatants and the HepG2/C3A cell lysates were determined via RT-qPCR. The capsid protein ORF2 was immunostained. The effect of ribavirin was also assessed. The HEV RNA concentrations in the supernatants and the cell lysates were higher for the variants harboring the RNF19A, ZNF787, KIF1B, RPS17, and EEF1A1 insertions than for the Kernow p6 del S17, while it was not with RNA18 or RPL6 fragments. The number of ORF2 foci was higher for RNF19A, ZNF787, KIF1B, and RPS17 than for Kernow p6 del S17. VHRVs with replicative advantages were less sensitive to the antiviral effect of ribavirin. No difference in PTMs was found between VHRVs with a replicative advantage and those without. In conclusion, our study showed that insertions did not systematically confer a replicative advantage in vitro. Further studies are needed to determine the mechanisms underlying the differences in replicative capacity. IMPORTANCE Hepatitis E virus (HEV) is a major cause of viral hepatitis. HEV can lead to chronic infection in immunocompromised patients. Ribavirin treatment is currently used to treat such chronic infections. Recently, seven virus-host recombinant viruses were characterized in immunocompromised patients. These viruses have incorporated a portion of a human gene fragment into their genome. We studied the consequences of these insertions on the replication capacity. We found that these inserted fragments could enhance virus replication for five of the seven recombinant variants. We also showed that the recombinant variants with replicative advantages were less sensitive to ribavirin in vitro. Finally, we found that the mechanisms leading to such a replicative advantage do not seem to rely on the post-translational modifications introduced by the human gene fragment that could have modified the function of the viral protein. The mechanisms involved in improving the replication of such recombinant viruses remain to be explored.
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Affiliation(s)
- Olivia Paronetto
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Claire Allioux
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Chloé Diméglio
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Lhorane Lobjois
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Nicolas Jeanne
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Noémie Ranger
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Jérôme Boineau
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Mélanie Pucelle
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sofia Demmou
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Florence Abravanel
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sabine Chapuy-Regaud
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Jacques Izopet
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sébastien Lhomme
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
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Solignac J, Boschi C, Pernin V, Fouilloux V, Motte A, Aherfi S, Fabre-Aubrespy M, Legris T, Brunet P, Colson P, Moal V. The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature. Virol J 2024; 21:136. [PMID: 38867299 PMCID: PMC11167830 DOI: 10.1186/s12985-024-02401-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Hepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation. CASE PRESENTATION Three weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment. DISCUSSION Seven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.
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Affiliation(s)
- Justine Solignac
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France
| | - Celine Boschi
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Vincent Pernin
- Department of Nephrology Dialysis and Kidney Transplantation, Lapeyronie University Hospital, Montpellier, France
- Institute for Regenerative Medicine and Biotherapy (IRMB), Montpellier, France
| | - Virginie Fouilloux
- Department of Congenital and Pediatric Cardiac Surgery, Timone Children's Hospital, Marseille, France
| | - Anne Motte
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Sarah Aherfi
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Maxime Fabre-Aubrespy
- Department of Orthopaedic Surgery, Sainte-Marguerite University Hospital, Marseille, France
| | - Tristan Legris
- Centre de Néphrologie Et Transplantation Rénale, Publique Hôpitaux de Marseille, Hôpital Conception, Marseille, France
| | - Philippe Brunet
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France
| | - Philippe Colson
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Valérie Moal
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France.
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France.
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47
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Cheung CY, Chan KM, Sridhar S. Rat hepatitis E in kidney transplant recipients: Case studies and review of literature. Transpl Infect Dis 2024; 26:e14266. [PMID: 38488801 DOI: 10.1111/tid.14266] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 06/19/2024]
Affiliation(s)
- Chi Yuen Cheung
- Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China
| | - Koon Ming Chan
- Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
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48
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Thorburn S, Majumdar A, Smibert O. Chronic hepatitis E masquerading as allograft rejection in a liver transplant recipient. Transpl Infect Dis 2024; 26:e14303. [PMID: 38775175 DOI: 10.1111/tid.14303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 06/19/2024]
Affiliation(s)
- Samuel Thorburn
- Department of Infectious Diseases and Immunology, Austin Health, Heidelberg, Victoria, Australia
| | - Avik Majumdar
- Victorian Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia
- The University of Melbourne, Melbourne, Victoria, Australia
| | - Olivia Smibert
- Department of Infectious Diseases and Immunology, Austin Health, Heidelberg, Victoria, Australia
- National Centre for Infections in Cancer, Peter McCallum Cancer Centre, Melbourne, Victoria, Australia
- Department of Infectious Diseases, Peter McCallum Cancer Centre, Melbourne, Victoria, Australia
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Marion O, Izopet J, Kamar N. Which Hepatitis E virus to worry about in our transplant patients. Transpl Infect Dis 2024; 26:e14285. [PMID: 38872417 DOI: 10.1111/tid.14285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/02/2024] [Accepted: 04/04/2024] [Indexed: 06/15/2024]
Affiliation(s)
- Olivier Marion
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
| | - Jacques Izopet
- Laboratory of Virology, Institut Fédératif de Biologie, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
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Niederhauser C, Gowland P, Widmer N, Amar EL Dusouqui S, Mattle-Greminger M, Gottschalk J, Frey BM. Prevalence of Acute Hepatitis E Virus Infections in Swiss Blood Donors 2018-2020. Viruses 2024; 16:744. [PMID: 38793625 PMCID: PMC11125967 DOI: 10.3390/v16050744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/26/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
INTRODUCTION Hepatitis E virus (HEV) genotype 3 is the major cause of acute viral hepatitis in several European countries. It is acquired mainly by ingesting contaminated pork, but has also been reported to be transmitted through blood transfusion. Although most HEV infections, including those via blood products, are usually self-limiting, they may become chronic in immunocompromised persons. It is thus essential to identify HEV-infected blood donations to prevent transmission to vulnerable recipients. AIMS Prior to the decision whether to introduce HEV RNA screening for all Swiss blood donations, a 2-year nationwide prevalence study was conducted. METHODS All blood donations were screened in pools of 12-24 samples at five regional blood donation services, and HEV RNA-positive pools were subsequently resolved to the individual donation index donation (X). The viral load, HEV IgG and IgM serology, and HEV genotype were determined. Follow-up investigations were conducted on future control donations (X + 1) and previous archived donations of the donor (X - 1) where available. RESULTS Between October 2018 and September 2020, 541,349 blood donations were screened and 125 confirmed positive donations were identified (prevalence 1:4331 donations). At the time of blood donation, the HEV RNA-positive individuals were symptom-free. The median viral load was 554 IU/mL (range: 2.01-2,500,000 IU/mL). Men (88; 70%) were more frequently infected than women (37; 30%), as compared with the sex distribution in the Swiss donor population (57% male/43% female, p < 0.01). Of the 106 genotyped cases (85%), all belonged to genotype 3. Two HEV sub-genotypes predominated; 3h3 (formerly 3s) and 3c. The remaining sub-genotypes are all known to circulate in Europe. Five 3ra genotypes were identified, this being a variant associated with rabbits. In total, 85 (68%) X donations were negative for HEV IgM and IgG. The remaining 40 (32%) were positive for HEV IgG and/or IgM, and consistent with an active infection. We found no markers of previous HEV in 87 of the 89 available and analyzed archive samples (X - 1). Two donors were HEV IgG-positive in the X - 1 donation suggesting insufficient immunity to prevent HEV reinfection. Time of collection of the 90 (72%) analyzed X + 1 donations varied between 2.9 and 101.9 weeks (median of 35 weeks) after X donation. As expected, none of those tested were positive for HEV RNA. Most donors (89; 99%) were positive for anti-HEV lgG/lgM (i.e., seroconversion). HEV lgM-positivity (23; 26%) indicates an often-long persistence of lgM antibodies post-HEV infection. CONCLUSION The data collected during the first year of the study provided the basis for the decision to establish mandatory HEV RNA universal screening of all Swiss blood donations in minipools, a vital step in providing safer blood for all recipients, especially those who are immunosuppressed.
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Affiliation(s)
- Christoph Niederhauser
- Interregional Blood Transfusion SRC, 3008 Berne, Switzerland; (P.G.)
- Institute of Infectious Disease, University of Berne, 3008 Berne, Switzerland
| | - Peter Gowland
- Interregional Blood Transfusion SRC, 3008 Berne, Switzerland; (P.G.)
| | - Nadja Widmer
- Interregional Blood Transfusion SRC, 3008 Berne, Switzerland; (P.G.)
| | | | - Maja Mattle-Greminger
- Regional Blood Transfusion SRC, 8952 Schlieren, Switzerland; (M.M.-G.); (J.G.); (B.M.F.)
| | - Jochen Gottschalk
- Regional Blood Transfusion SRC, 8952 Schlieren, Switzerland; (M.M.-G.); (J.G.); (B.M.F.)
| | - Beat M. Frey
- Regional Blood Transfusion SRC, 8952 Schlieren, Switzerland; (M.M.-G.); (J.G.); (B.M.F.)
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