|
1
|
Karnsakul W, Schwarz KB. Hepatitis. REMINGTON AND KLEIN'S INFECTIOUS DISEASES OF THE FETUS AND NEWBORN INFANT 2025:728-744.e4. [DOI: 10.1016/b978-0-323-79525-8.00036-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
2
|
Wu J, Wang H, Xiang Z, Jiang C, Xu Y, Zhai G, Ling Z. Role of viral hepatitis in pregnancy and its triggering mechanism. J Transl Int Med 2024; 12:344-354. [PMID: 39360164 PMCID: PMC11444475 DOI: 10.2478/jtim-2024-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Abstract
Hepatitis viral infection can cause severe complications, even mortality in pregnant women and their offspring. Multiple studies have shown that vertical transmission can cause viral hepatitis infections in newborns, especially in hepatitis B, C, and E. Screening for hepatitis viral infection in pregnant women is essential. Once infected, pregnant women should be given timely antiviral treatments, which could effectively alleviate the disease progression and reduce adverse outcomes. Besides, the mechanism of viral hepatitis mediating adverse pregnancy outcomes has been a hot topic. Hepatitis B virus has been found to mediate both mother- to-child and parent-child transmission. Liver injury in hepatitis C virus infection is associated with immune-mediated mechanisms, which can be regulated by hormonal factors as well. The mediating mechanism of adverse maternal and infant outcomes caused by hepatitis E virus infection is mainly related to viral replication in the placenta and changes in cytokine and estrogen. Nevertheless, the specific mechanisms related to hepatitis A virus and hepatitis D virus remain unclear, and more research is needed. This review shows that the existence of viral hepatitis during pregnancy can pose certain risks for pregnant women and infants, and different interventions have been used to treat pregnant women infected with viral hepatitis. It may provide deep insight into adverse pregnancy outcomes caused by viral hepatitis and give guidance on treatment.
Collapse
Affiliation(s)
- Jian Wu
- Department of Blood Transfusion, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou 215008, Jiangsu Province, China
| | - Huiqing Wang
- Department of Family Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
| | - Ze Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, City, Hangzhou 310003, Zhejiang Province, China
| | - Chun Jiang
- Department of Blood Transfusion, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou 215008, Jiangsu Province, China
| | - Yunyang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, City, Hangzhou 310003, Zhejiang Province, China
| | - Guanghua Zhai
- Department of Blood Transfusion, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou 215008, Jiangsu Province, China
| | - Zongxin Ling
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, City, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Liang Y, Zhang J, Luo D, Cheng L, Wang Y. Deregulation of immune response contributing to fulminant hepatitis in HEV infected pregnant women. J Med Virol 2024; 96:e29639. [PMID: 38708824 DOI: 10.1002/jmv.29639] [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: 12/30/2023] [Revised: 03/23/2024] [Accepted: 04/19/2024] [Indexed: 05/07/2024]
Abstract
Hepatitis E virus (HEV) infection in pregnant women is associated with a wide spectrum of adverse consequences for both mother and fetus. The high mortality in this population appears to be associated with hormonal changes and consequent immunological changes. This study conducted an analysis of immune responses in pregnant women infected with HEV manifesting varying severity. Data mining analysis of the GSE79197 was utilized to examine differentially biological functions in pregnant women with HEV infection (P-HEV) versus without HEV infection (P-nHEV), P-HEV progressing to ALF (P-ALF) versus P-HEV, and P-HEV versus non-pregnant women with HEV infection (nP-HEV). We found cellular response to interleukin and immune response-regulating signalings were activated in P-HEV compared with P-nHEV. However, there was a significant decrease of immune responses, such as T cell activation, leukocyte cell-cell adhesion, regulation of lymphocyte activation, and immune response-regulating signaling pathway in P-ALF patient than P-HEV patient. Compared with nP-HEV, MHC protein complex binding function was inhibited in P-HEV. Further microRNA enrichment analysis showed that MAPK and T cell receptor signaling pathways were inhibited in P-HEV compared with nP-HEV. In summary, immune responses were activated during HEV infection while being suppressed when developing ALF during pregnancy, heightening the importance of immune mediation in the pathogenesis of severe outcome in HEV infected pregnant women.
Collapse
Affiliation(s)
- Yining Liang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, China
| | - Jiayue Zhang
- School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, Jiangsu, China
| | - Dehong Luo
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, China
| | - Lixin Cheng
- School of Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University, Shenzhen, Guangdong, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| |
Collapse
|
|
6
|
Cong C, Xia Y, Gong S, Li T, Liu H, Zhong G, Chen D, Zhao W, Yu W, Yao Y, Liu J, Wei D, Cao H, Huang F. Infectious hepatitis E virus excreted into the vagina. FASEB J 2024; 38:e23500. [PMID: 38441537 DOI: 10.1096/fj.202301519rr] [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: 07/26/2023] [Revised: 01/25/2024] [Accepted: 02/06/2024] [Indexed: 03/07/2024]
Abstract
Hepatitis E virus (HEV) persists in the male genital tract that associates with infertility. However, the presence of HEV in the female genital tract is unreported. Vaginal secretions, cervical smears, and cervix uteri were collected to explore the presence of HEV in the female genital tract. HEV RNA and/or antigens were detected in the vaginal secretions, cervical smears, and the cervix uteri of women. The infectivity of HEV excreted into vaginal secretions was further validated in vitro. In addition, HEV replicates in the female genital tract were identified in HEV-infected animal models by vaginal injection or vaginal mucosal infection to imitate sexual transmission. Serious genital tract damage and inflammatory responses with significantly elevated mucosal innate immunity were observed in women or animals with HEV vaginal infection. Results demonstrated HEV replicates in the female genital tract and causes serious histopathological damage and inflammatory responses.
Collapse
Affiliation(s)
- Chao Cong
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Yueping Xia
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Shilin Gong
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Tengyuan Li
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Huichan Liu
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Guo Zhong
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Dongxue Chen
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Wanqiu Zhao
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
| | - Yinjie Yao
- Kunming City Maternal and Child Health Hospital, Kunming, PR China
| | - Jiankun Liu
- 920th Hospital of the PLA Joint Logistics Support Force, Kunming, PR China
| | - Daqiao Wei
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Fen Huang
- School of Medicine, The Academy for Cells and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, PR China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| |
Collapse
|
|
7
|
Zhang S, Ye X, Lin X, Zeng X, Meng S, Luo W, Yu F, Peng T, Huang T, Li J, Hu Z. Novel insights into aerobic 17β-estradiol degradation by enriched microbial communities from mangrove sediments. JOURNAL OF HAZARDOUS MATERIALS 2024; 465:133045. [PMID: 38016312 DOI: 10.1016/j.jhazmat.2023.133045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/13/2023] [Accepted: 11/18/2023] [Indexed: 11/30/2023]
Abstract
Various persistent organic pollutants (POPs) including estrogens are often enriched in mangrove regions. This research investigated the estrogens pollution levels in six mangroves located in the Southern China. The estrogen levels were found to be in the range of 5.3-24.9 ng/g dry weight, suggesting that these mangroves had been seriously contaminated. The bacterial communities under estrogen stress were further enriched by supplementing 17β-estradiol (E2) as the sole carbon source. The enriched bacterial communities showed an excellent E2 degradation capacity > 95 %. These communities were able to transform E2 into estrone (E1), 4-hydroxy-estrone, and keto-estrone, etc. 16 S rDNA sequencing and metagenomics analysis revealed that bacterial taxa Oleiagrimonas, Pseudomonas, Terrimonas, and Nitratireductor etc. were the main contributors to estrogen degradation. Moreover, the genes involved in E2 degradation were enriched in the microbial communities, including the genes encoding 17β-hydroxysteroid dehydrogenase, estrone 4-hydroxylase, etc. Finally, the analyses of functional genes and binning genomes demonstrated that E2 was degraded by bacterial communities via dehydrogenation into E1 by 17β-hydroxysteroid dehydrogenase. E1 was then catabolically converted to 3aα-H-4α(3'-propanoate)- 7aβ-methylhexahydro-1,5-indanedione via 4,5-seco pathway. Alternatively, E1 could also be hydroxylated to keto-estrone, followed by B-ring cleavage. This study provides novel insights into the biodegradation of E2 by the bacterial communities in estrogen-contaminated mangroves.
Collapse
Affiliation(s)
- Shan Zhang
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Xueying Ye
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China; School of Life Sciences, Huizhou University, Huizhou 510607, China
| | - Xianbin Lin
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Xiangwei Zeng
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Shanshan Meng
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Wenqi Luo
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Fei Yu
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Tao Peng
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Tongwang Huang
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China
| | - Jin Li
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China; College of Life Sciences, China West Normal University, Nanchong 637002, China.
| | - Zhong Hu
- Department of Biology, Shantou University, Shantou, Guangdong 515063, China.
| |
Collapse
|
|
8
|
Khuroo MS. Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story. Viruses 2023; 15:1745. [PMID: 37632090 PMCID: PMC10459142 DOI: 10.3390/v15081745] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine.
Collapse
Affiliation(s)
- Mohammad Sultan Khuroo
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Jammu & Kashmir 190010, India
| |
Collapse
|
|
9
|
Qian Z, Li T, Xia Y, Cong C, Chen S, Zhang Y, Gong S, Wang W, Liu H, Chen D, Zhao W, Zhong G, Deng Y, Yu W, Wei D, Yu X, Huang F. Genotype 4 Hepatitis E virus replicates in the placenta, causes severe histopathological damage, and vertically transmits to fetuses. J Infect 2023; 87:34-45. [PMID: 37160209 DOI: 10.1016/j.jinf.2023.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/17/2023] [Accepted: 05/03/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection in pregnant women causes adverse pregnancy outcomes, including maternal death, premature delivery, stillbirth, and fetal infection. However, the pathogenesis of maternal and fetal HEV infection is unclear. METHODS Placenta and placental appendixes were collected from HEV-4 infected pregnant women to explore the vertical transmission of HEV from mothers to fetuses. RESULTS HEV-4 replicated in the placenta, placental membrane, and umbilical cord and was vertically transmitted from mothers to fetuses. HEV-4 placental infection resulted in serious histopathological damage, such as fibrosis and calcification, and severe inflammatory responses. Adverse maternal outcomes were observed in 38.5% of HEV-4 infected pregnant women. The distinct cytokine/chemokine expression patterns of HEV-infected pregnant women and nonpregnant women may contribute to the adverse pregnancy outcomes. Furthermore, the impaired maternal and fetal innate immune responses against HEV-4 facilitated viral replication during pregnancy. CONCLUSION HEV-4 replicates in the placenta and is vertically transmitted from mothers to fetuses, causing severe histopathological damage.
Collapse
Affiliation(s)
- Zhongyao Qian
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Tengyuan Li
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Yueping Xia
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Chao Cong
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shuangfeng Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Yike Zhang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shiling Gong
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenjing Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Huichan Liu
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Dongxue Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wanqiu Zhao
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Guo Zhong
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Yinlong Deng
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China.
| | - Daqiao Wei
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China.
| | - Xiongwu Yu
- Qujing Maternal and Child Health-care Hospital Affiliated Hospital of Kunming University of Science and Technology, Qujing, PR China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China; Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, PR China.
| |
Collapse
|
|
10
|
Qian Z, Cong C, Li Y, Bi Y, He Q, Li T, Xia Y, Xu L, Mickael HK, Yu W, Liu J, Wei D, Huang F. Quantification of host proteomic responses to genotype 4 hepatitis E virus replication facilitated by pregnancy serum. Virol J 2023; 20:111. [PMID: 37264422 PMCID: PMC10233519 DOI: 10.1186/s12985-023-02080-5] [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: 01/31/2022] [Accepted: 05/23/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is a common cause of acute hepatitis worldwide and causes approximately 30% case fatality rate among pregnant women. Pregnancy serum (PS), which contains a high concentration of estradiol, facilitates HEV replication in vitro through the suppression of the PI3K-AKT-mTOR and cAMPK-PKA-CREB signaling pathways. However, the proteomics of the complex host responses to HEV infection, especially how PS facilitates viral replication, remains unclear. METHODS In this study, the differences in the proteomics of HEV-infected HepG2 cells supplemented with fetal bovine serum (FBS) from those of HEV-infected HepG2 cells supplemented with serum from women in their third trimester of pregnancy were quantified by using isobaric tags for relative and absolute quantification technology. RESULTS A total of 1511 proteins were identified, among which 548 were defined as differentially expressed proteins (DEPs). HEV-infected cells supplemented with PS exhibited the most significant changes at the protein level. A total of 328 DEPs, including 66 up-regulated and 262 down-regulated proteins, were identified in HEV-infected cells supplemented with FBS, whereas 264 DEPs, including 201 up-regulated and 63 down-regulated proteins, were found in HEV-infected cells supplemented with PS. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that in HEV-infected cells, PS supplementation adjusted more host genes and signaling pathways than FBS supplementation. The DEPs involved in virus-host interaction participated in complex interactions, especially a large number of immune-related protein emerged in HEV-infected cells supplemented with PS. Three significant or interesting proteins, including filamin-A, thioredoxin, and cytochrome c, in HEV-infected cells were functionally verified. CONCLUSIONS The results of this study provide new and comprehensive insight for exploring virus-host interactions and will benefit future studies on the pathogenesis of HEV in pregnant women.
Collapse
Affiliation(s)
- Zhongyao Qian
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Chao Cong
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yi Li
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yanhong Bi
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Qiuxia He
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Tengyuan Li
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yueping Xia
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Liangheng Xu
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Houfack K Mickael
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China.
| | - Jiankun Liu
- 920th Hospital of Joint Logistics Support Force of PLA, Kunming, People's Republic of China.
| | - Daqiao Wei
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China.
| | - Fen Huang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China.
| |
Collapse
|
|
11
|
Mahsoub HM, Heffron CL, Hassebroek AM, Sooryanarain H, Wang B, LeRoith T, Rodríguez GR, Tian D, Meng XJ. Fetal Loss in Pregnant Rabbits Infected with Genotype 3 Hepatitis E Virus Is Associated with Altered Inflammatory Responses, Enhanced Virus Replication, and Extrahepatic Virus Dissemination with Positive Correlations with Increased Estradiol Level. mBio 2023; 14:e0041823. [PMID: 36939322 PMCID: PMC10128027 DOI: 10.1128/mbio.00418-23] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 02/24/2023] [Indexed: 03/21/2023] Open
Abstract
Hepatitis E virus (HEV) causes adverse clinical outcomes in pregnant women, but the underlying mechanisms remain poorly understood. To delineate the mechanisms of pregnancy-associated adverse effects during HEV infection, we utilized a genotype 3 HEV from rabbit (HEV-3ra) and its cognate host (rabbits) to systematically investigate the clinical consequences, viral replication dynamics, and host immune and hormonal responses of HEV infection during pregnancy. We found a significant fetal loss of 23% in HEV-infected pregnant rabbits, indicating an early-stage miscarriage. HEV infection in pregnant rabbits was characterized by higher viral loads in feces, intestinal contents, liver, and spleen tissues, as well as a longer and earlier onset of viremia than in infected nonpregnant rabbits. HEV infection altered the pattern of cytokine gene expressions in the liver of pregnant rabbits and caused a transient increase of serum interferon gamma (IFN-γ) shortly after a notable increase in viral replication, which may contribute to early fetal loss. Histological lesions in the spleen were more pronounced in infected pregnant rabbits, although moderate liver lesions were seen in both infected pregnant and nonpregnant rabbits. Total bilirubin was elevated in infected pregnant rabbits. The serum levels of estradiol (E2) in HEV-infected pregnant rabbits were significantly higher than those in mock-infected pregnant rabbits at 14 days postinoculation (dpi) and correlated positively with higher viral loads in feces, liver, and spleen tissues at 28 dpi, suggesting that it may play a role in extrahepatic virus dissemination. The results have important implications for understanding the severe diseases associated with HEV infection during pregnancy. IMPORTANCE HEV causes adverse pregnancy outcomes, with a mortality rate of >30% in pregnant women, but the underlying mechanisms are poorly understood. In this study, we utilized HEV-3ra and its cognate host (pregnant rabbit) to delineate the potential underlying mechanisms of pregnancy-associated adverse outcomes during HEV infection. We found that infected pregnant rabbits had a fetal loss of 23%, which coincided with enhanced viral replication and an elevated systemic IFN-γ response, followed by longer viremia duration and extrahepatic viral dissemination. Estradiol levels were increased in infected pregnant rabbits and correlated positively with higher fecal viral shedding and higher viral loads in liver and spleen tissues. Infected pregnant rabbits had more pronounced splenic lesions, higher serum total bilirubin, and an altered cytokine gene expression profile in the liver. The results will contribute to our understanding of the mechanisms of HEV-associated adverse pregnancy outcomes.
Collapse
Affiliation(s)
- 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, Fralin Life Sciences Institute, 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Anna M. Hassebroek
- 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Harini Sooryanarain
- 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Tanya LeRoith
- 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Guillermo Raimundi Rodríguez
- 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, Fralin Life Sciences Institute, 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, Fralin Life Sciences Institute, 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, Fralin Life Sciences Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| |
Collapse
|
|
12
|
Xia Y, Yang W, Li Y, Qian Z, Chen S, Zhang Y, Cong C, Li T, Liu H, Chen D, Zhao W, Zhong G, Wei D, Yu W, Huang F. Severe maternal-fetal pathological damage and inflammatory responses contribute to miscarriage caused by hepatitis E viral infection during pregnancy. Liver Int 2023; 43:317-328. [PMID: 36305303 DOI: 10.1111/liv.15468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 09/04/2022] [Accepted: 10/25/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection causes serious adverse pregnancy outcomes during pregnancy. However, the maternal and fetal damage induced by HEV infection is rarely reported. METHODS A BALB/c pregnant mouse model was established to explore the maternal and fetal pathological damage and inflammatory responses caused by HEV infection. RESULTS Notably, miscarriages and stillbirths were observed in HEV-infected pregnant mice. HEV infections were identified by qRT-PCR, immunohistochemical analysis and immunofluorescence assay in the uterus, placenta, umbilical cords and livers and brains of fetuses. Serious inflammatory responses and pathological damage were triggered in the uterus and placenta of HEV-infected pregnant mice. Vertical transmission of HEV resulted in severe pathological damage and inflammatory responses in the livers and brains of fetuses, as well as emerging apoptosis cells in the brains of fetuses. Most of the cytokines/chemokines in the sera were significantly increased in the HEV-infected pregnant mice. Remarkably, cytokines/chemokines were significantly different between HEV-infected pregnant and miscarriage mice; IL9, GM-CSF and IL1α were the most important three cytokines/chemokines in determining the pregnancy outcomes. CONCLUSION HEV infections cause serious maternal/fetal pathological damage, inflammatory responses and apoptosis, which may be responsible for adverse pregnancy outcomes.
Collapse
Affiliation(s)
- Yueping Xia
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Weimin Yang
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yi Li
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Zhongyao Qian
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Shuangfeng Chen
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yike Zhang
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Chao Cong
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Tengyuan Li
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Huichan Liu
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Dongxue Chen
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Wanqiu Zhao
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Guo Zhong
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Daqiao Wei
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China
| | - Fen Huang
- Life Science and Technology & Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China.,Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, People's Republic of China
| |
Collapse
|
|
13
|
Prevalence of hepatitis E virus and its association with adverse pregnancy outcomes in pregnant women in China. J Clin Virol 2023; 158:105353. [PMID: 36527809 DOI: 10.1016/j.jcv.2022.105353] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/12/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection has become a global concern, especially in pregnant women. However, the association between HEV prevalence and age, gravidity and parity of pregnant women remains unclear. METHODS Pregnant women (n=19,762) were enrolled for HEV prevalence and associated adverse pregnancy outcomes investigation in Qujing City, Yunnan Province of China from May 2019 to December 2020. RESULTS The seroprevalence of HEV was 11.6% (2,297/19,762; 95% CI:11.2%-12.1%). About 11.4% (2,247/19,762; 95% CI:10.9%-11.8%) were positive for anti-HEV IgG antibody, 0.1% (22/19,762; 95% CI:0.1%-0.2%) were positive for anti-HEV IgM antibody, and 0.1% (28/19,762; 95% CI:0.1%-0.2%) were positive for both anti-HEV IgM and IgG antibodies. Sixty-one out of 2,297 anti-HEV-antibodies-positive pregnant women were positive for HEV RNA. Phylogenetic analysis revealed that all HEV isolates from pregnant women belong to genotype 4. Age, gravidity and parity are associated with increased prevalence of HEV. Pregnant women positive for HEV-IgG antibody bear a higher risk for an adverse pregnancy history and liver injury with elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels than anti-HEV-negative pregnant women. Furthermore, seropositive pregnant women suffered a higher adverse maternal outcomes risk (crude odds ratio [cOR]=1.29; 95% CI: 1.16-1.43; adjusted odds ratio [aOR]=1.40, 95% CI: 1.25-1.55 for anti-HEV-IgG-positive pregnant women and cOR=1.38, 95% CI: 1.02-1.86; aOR=1.43, 95% CI: 1.05-1.95 for anti-HEV-IgM-positive pregnant women) and fetal outcomes risk (cOR=1.80, 95% CI: 1.61-2.01; aOR=1.77, 95% CI: 1.57-1.99) than anti-HEV-negative pregnant women. Adverse pregnancy outcomes of HEV infection are aggravated by age, gravidity and parity. CONCLUSION In this study, we demonstrated high prevalence of HEV in pregnancy women in China, and HEV infection can cause various adverse maternal and neonatal outcomes.
Collapse
|
|
14
|
Tian K, Meng Q, Li S, Chang M, Meng F, Yu Y, Li H, Qiu Q, Shao J, Huo H. Mechanism of 17β-estradiol degradation by Rhodococcus equi via the 4,5-seco pathway and its key genes. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 312:120021. [PMID: 36037852 DOI: 10.1016/j.envpol.2022.120021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 08/04/2022] [Accepted: 08/17/2022] [Indexed: 06/15/2023]
Abstract
Steroid estrogens have been detected in oceans, rivers, lakes, groundwaters, soils, and even urban water supply systems, thereby inevitably imposing serious impacts on human health and ecological safety. Indeed, many estrogen-degrading bacterial strains and degradation pathways have been reported, with the 4,5-seco pathway being particularly important. However, few studies have evaluated the use of the 4,5-seco pathway by actinomycetes to degrade 17β-estradiol (E2). In this study, 5 genes involved in E2 degradation were identified in the Rhodococcus equi DSSKP-R-001 (R-001) genome and then heterologously expressed to confirm their functions. The transformation of E2 with hsd17b14 reached 63.7% within 30 h, resulting in transformation into estrone (E1). Furthermore, we found that At1g12200-encoded flavin-binding monooxygenase (FMOAt1g12200) can transform E1 at a rate of 51.6% within 30 h and can transform E1 into 4-hydroxyestrone (4-OH E1). In addition, catA and hsaC genes were identified to further transform 4-OH E1 at a rate of 97-99%, and this reaction was accomplished by C-C cleavage at the C4 position of the A ring of 4-OH E1. This study represents the first report on the roles of these genes in estrogen degradation and provides new insights into the mechanisms of microbial estrogen metabolism and a better understanding of E2 degradation via the 4,5-seco pathway by actinomycetes.
Collapse
Affiliation(s)
- Kejian Tian
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Qi Meng
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Shuaiguo Li
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Menghan Chang
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Fanxing Meng
- Jilin Province Water Resources and Hydropower Consultative Company of PR China, Changchun City, Jilin Province, China
| | - Yue Yu
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Han Li
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Qing Qiu
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Junhua Shao
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China
| | - Hongliang Huo
- School of Environment, Northeast Normal University, No. 2555 Jingyue Avenue, Changchun City, Jilin Province, China; Jilin Province Laboratory of Water Pollution Control and Resource Engineering, Changchun, 130117, China.
| |
Collapse
|
|
15
|
Modulation of SOCS3 Levels via STAT3 and Estrogen-ERαp66 Signaling during Hepatitis E Virus Replication in Hepatocellular Carcinoma Cells. J Virol 2022; 96:e0100822. [PMID: 36102649 PMCID: PMC9555149 DOI: 10.1128/jvi.01008-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Hepatitis E virus (HEV) infection usually results in a self-limiting acute disease; however, in infected pregnant women, it is associated with increased mortality and fulminant hepatic failure. Estrogen is known to be elevated during pregnancy, and estrogen signaling via classical estrogen receptor-ERα is known to regulate hepatocyte function and host innate immune response, including the STAT3 pathway. In this study, we investigated whether the estrogen classical signaling pathway via ERαp66 has any effect on STAT3 activation during HEV replication and HEV-induced IFN response. We first demonstrated that Huh7-S10-3 liver cells expressed the nonfunctional estrogen receptor ERαp36 isoform and lack the functional ERαp66 isoform. We further showed persistent phosphorylated-STAT3 levels in genotype 3 human HEV (Kernow P6 strain) RNA-transfected cells at later time points. In Huh7-S10-3 cells, estrogen at first-to-third trimester concentration (7.3 to 73 nM) did not significantly affect HEV replication; however, blocking of STAT3 activation led to a decrease in the HEV ORF2 protein level. Our mechanistic study revealed that STAT3 differentially regulates SOCS3 and type-III interferon (IFN) levels during HEV replication and the presence of estrogen-ERαp66 signaling stabilizes SOCS3 levels in vitro. We also demonstrate that HEV infection in pregnant and nonpregnant rabbits led to a significant increase in IFN response as measured by increased levels of IFN-stimulated-gene-15 (ISG15) mRNA levels irrespective of pregnancy status. Collectively, the results indicate that estrogen signaling and STAT3 regulate SOCS3 and IFN responses in vitro during HEV replication. The results have important implications for understanding HEV replication and HEV-induced innate immune response in pregnant women. IMPORTANCE Hepatitis E is usually a self-resolving acute disease; however, in pregnant women, HEV infection is associated with high mortality and fulminant hepatic failure. During pregnancy, estrogen levels are elevated, and in the liver, the estrogen receptor ERα is predominant and estrogen signaling is known to regulate hepatocyte metabolism and leptin-induced STAT3 levels. Viruses can module host innate immune response via STAT3. Therefore, in this study, we investigated whether STAT3 and estrogen-classical signaling via the ERαp66 pathway modulate HEV replication and HEV-induced innate immune response. We demonstrated that estrogen signaling did not affect HEV replication in human liver cells, but blocking of STAT3 activation reduced HEV capsid protein levels in human liver cells. We also showed that inhibition of STAT3 activation reduced SOCS3 levels, while the presence of the estrogen-ERαp66 signaling pathway stabilized SOCS3 levels. The results from this study will aid our understanding of the mechanism of HEV pathogenesis and immune response during pregnancy.
Collapse
|
|
16
|
Uterine Injury Caused by Genotype 4 Hepatitis E Virus Infection Based on a BALB/c Mice Model. Viruses 2021; 13:v13101950. [PMID: 34696377 PMCID: PMC8538062 DOI: 10.3390/v13101950] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/15/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022] Open
Abstract
To evaluate whether uterine injury caused by hepatitis E virus (HEV) infection is responsible for adverse pregnancy outcomes. HEV-infected female BALB/c mice were coupled with healthy male BALB/c mice at 0, 7, 14, 21, and 91 dpi to explore the uterine injury caused by HEV infection. Mice were euthanized after 10 days of copulation, and uteruses were collected for HEV RNA and antigen detection and histopathological analysis. Inflammatory responses; apoptosis; and estrogen receptor ɑ (ER-ɑ), endomethal antibody (ERAb), cytokeratin-7 (CK7), vimentin (VIM), and vascular endothelial growth factor (VEGF) expression levels were evaluated. After 10 days of copulation, miscarriage and nonpregnancy, as well as enlarged uteruses filled with inflammatory cytokines, were found in HEV-infected mice. HEV RNA and antigens were detected in the sera and uteruses of HEV-infected mice. Significant endometrial thickness (EMT) thinning, severe inflammatory responses, and aggravated apoptosis in the uteruses of HEV-infected mice that experienced miscarriage might contribute to adverse pregnancy outcomes. Furthermore, significantly suppressed ER-ɑ expression and increased ERAb, CK7, VIM, and VEGF expression levels were found in the uteruses of HEV-infected mice that had miscarried. However, uterine damage recovered after complete HEV clearance, and impaired fertility was improved. EMT injury, severe inflammatory responses, and aggravated apoptosis in the uterus caused by HEV infection are responsible for poor pregnancy outcomes.
Collapse
|
|
17
|
Yadav KK, Kenney SP. Hepatitis E Virus Immunopathogenesis. Pathogens 2021; 10:pathogens10091180. [PMID: 34578211 PMCID: PMC8465319 DOI: 10.3390/pathogens10091180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/05/2021] [Accepted: 09/06/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus is an important emerging pathogen producing a lethal impact on the pregnant population and immunocompromised patients. Starting in 1983, it has been described as the cause for acute hepatitis transmitted via the fecal–oral route. However, zoonotic and blood transfusion transmission of HEV have been reported in the past few decades, leading to the detailed research of HEV pathogenesis. The reason behind HEV being highly virulent to the pregnant population particularly during the third trimester, leading to maternal and fetal death, remains unknown. Various host factors (immunological, nutritional, hormonal) and viral factors have been studied to define the key determinants assisting HEV to be virulent in pregnant and immunocompromised patients. Similarly, chronic hepatitis is seen particularly in solid organ transplant patients, resulting in fatal conditions. This review describes recent advances in the immunopathophysiology of HEV infections in general, pregnant, and immunocompromised populations, and further elucidates the in vitro and in vivo models utilized to understand HEV pathogenesis.
Collapse
|
|
18
|
Kupke P, Werner JM. Hepatitis E Virus Infection-Immune Responses to an Underestimated Global Threat. Cells 2021; 10:cells10092281. [PMID: 34571931 PMCID: PMC8468229 DOI: 10.3390/cells10092281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.
Collapse
|
|
19
|
Khuroo MS. Hepatitis E and Pregnancy: An Unholy Alliance Unmasked from Kashmir, India. Viruses 2021; 13:1329. [PMID: 34372535 PMCID: PMC8310059 DOI: 10.3390/v13071329] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 06/22/2021] [Accepted: 07/05/2021] [Indexed: 12/23/2022] Open
Abstract
The adverse relationship between viral hepatitis and pregnancy in developing countries had been interpreted as a reflection of retrospectively biased hospital-based data collection by the West. However, the discovery of hepatitis E virus (HEV) as the etiological agent of an epidemic of non-A, non-B hepatitis in Kashmir, and the documenting of the increased incidence and severity of hepatitis E in pregnancy via a house-to-house survey, unmasked this unholy alliance. In the Hepeviridae family, HEV-genotype (gt)1 from genus Orthohepevirus A has a unique open reading frame (ORF)4-encoded protein which enhances viral polymerase activity and viral replication. The epidemics caused by HEV-gt1, but not any other Orthohepevirus A genotype, show an adverse relationship with pregnancy in humans. The pathogenesis of the association is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the pregnant women including infection and damage to the maternal-fetal interface by HEV-gt1; vertical transmission of HEV to fetus causing severe fetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the pregnant women, promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of acute liver failure. (ALF). Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.
Collapse
Affiliation(s)
- Mohammad Sultan Khuroo
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Jammu and Kashmir 190010, India
| |
Collapse
|
|
20
|
Ji H, Chen S, He Q, Wang W, Gong S, Qian Z, Zhang Y, Wei D, Yu W, Huang F. The different replication between nonenveloped and quasi-enveloped hepatitis E virus. J Med Virol 2021; 93:6267-6277. [PMID: 34076903 DOI: 10.1002/jmv.27121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 12/15/2022]
Abstract
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. However, the understanding of the HEV life cycle is limited. In the present study, cells were separately infected with nonenveloped HEV (derived from feces or bile) or quasi-enveloped HEV (derived from the cell culture after serial passages, eHEV) and observed by confocal fluorescence microscopy to investigate the life cycle of HEV. HEV finished its binding and entry into host cells at first 6 h postinoculation (hpi). Cells inoculated with eHEV showed less infectivity than cells inoculated with nonenveloped HEV. Newly synthesized progeny virions were released into the supernatant of cell cultures from 48 hpi. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis results showed that the supernatant's progeny viruses were infectious even after five serial passages. These results show the significant difference between nonenveloped HEV and eHEV, which will provide novel insights into the HEV replication cycle. The efficient cell culture of HEV will promote the development of anti-HEV drugs and vaccines.
Collapse
Affiliation(s)
- Hanbin Ji
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shuangfeng Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Qiuxia He
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenjing Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shilin Gong
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Zhongyao Qian
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Yike Zhang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Daqiao Wei
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China.,Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, PR China
| |
Collapse
|
|
21
|
Gong S, Hao X, Bi Y, Yang C, Wang W, Mickael HK, Zhang Y, Chen S, Qian Z, Huang F, Wei D, Yu W. Hepatitis E viral infection regulates estrogen signaling pathways: Inhibition of the cAMPK-PKA-CREB and PI3K-AKT-mTOR signaling pathways. J Med Virol 2021; 93:3769-3778. [PMID: 33128390 DOI: 10.1002/jmv.26641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 10/17/2020] [Accepted: 10/25/2020] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) infection has become a global concern with high mortality rates among pregnant women, especially those in their third trimester of pregnancy. Estrogen plays an important role in mediating the body, regulating physiological and pathological processes. Estrogen is activated by binding to estrogen receptors (ERs) and mediates rapid signaling events by pathways that involve transmembrane ERs. Our previous study had confirmed that high estrogen levels during pregnancy are associated with high HEV titers. However, the association between HEV infection and estrogen signaling pathways remains unclear. In the present study, the regulation of estrogen signaling pathways by HEV infection was evaluated. Results demonstrated that HEV infection significantly inhibits the cAMP-PKA-CREB and PI3K-AKT-mTOR signaling pathways, but is independent of the Ras-Raf-MEK-ERK signaling pathway. In summary, the increasing estrogen levels and highly activated ERα during pregnancy aggravates HEV replication. The exacerbation of HEV replication, in turn, inhibits ERα expression and suppresses both cAMP-PKA-CREB and PI3K-AKT-mTOR signaling pathways.
Collapse
Affiliation(s)
- Shilin Gong
- Medical School, Kunming University of Science and Technology, Kunming, PR China
- Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, PR China
| | - Xianhui Hao
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Yanhong Bi
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Chenchen Yang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Wenjing Wang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Houfack K Mickael
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Yike Zhang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Shuangfeng Chen
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Zhongyao Qian
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Fen Huang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
- Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, PR China
| | - Daqiao Wei
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
| |
Collapse
|
|
22
|
Advances in Hepatitis E Virus Biology and Pathogenesis. Viruses 2021; 13:v13020267. [PMID: 33572257 PMCID: PMC7915517 DOI: 10.3390/v13020267] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/21/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is one of the causative agents for liver inflammation across the world. HEV is a positive-sense single-stranded RNA virus. Human HEV strains mainly belong to four major genotypes in the genus Orthohepevirus A, family Hepeviridae. Among the four genotypes, genotype 1 and 2 are obligate human pathogens, and genotype 3 and 4 cause zoonotic infections. HEV infection with genotype 1 and 2 mainly presents as acute and self-limiting hepatitis in young adults. However, HEV infection of pregnant women with genotype 1 strains can be exacerbated to fulminant hepatitis, resulting in a high rate of case fatality. As pregnant women maintain the balance of maternal-fetal tolerance and effective immunity against invading pathogens, HEV infection with genotype 1 might dysregulate the balance and cause the adverse outcome. Furthermore, HEV infection with genotype 3 can be chronic in immunocompromised patients, with rapid progression, which has been a challenge since it was reported years ago. The virus has a complex interaction with the host cells in downregulating antiviral factors and recruiting elements to generate a conducive environment of replication. The virus-cell interactions at an early stage might determine the consequence of the infection. In this review, advances in HEV virology, viral life cycle, viral interference with the immune response, and the pathogenesis in pregnant women are discussed, and perspectives on these aspects are presented.
Collapse
|
|
23
|
Terrault NA, Levy MT, Cheung KW, Jourdain G. Viral hepatitis and pregnancy. Nat Rev Gastroenterol Hepatol 2021; 18:117-130. [PMID: 33046891 DOI: 10.1038/s41575-020-00361-w] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
The management of viral hepatitis in the setting of pregnancy requires special consideration. There are five liver-specific viruses (hepatitis A, B, C, D, E), each with unique epidemiology, tendency to chronicity, risk of liver complications and response to antiviral therapies. In the setting of pregnancy, the liver health of the mother, the influence of pregnancy on the clinical course of the viral infection and the effect of the virus or liver disease on the developing infant must be considered. Although all hepatitis viruses can harm the mother and the child, the greatest risk to maternal health and subsequently the fetus is seen with acute hepatitis A virus or hepatitis E virus infection during pregnancy. By contrast, the primary risks for hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus are related to the severity of the underlying liver disease in the mother and the risk of mother-to-child transmission (MTCT) for HBV and HCV. The prevention of MTCT is key to reducing the global burden of chronic viral hepatitis, and prevention strategies must take into consideration local health-care and socioeconomic challenges. This Review presents the epidemiology of acute and chronic viral hepatitis infection in pregnancy, the effect of pregnancy on the course of viral infection and, conversely, the influence of the viral infection on maternal and infant outcomes, including MTCT.
Collapse
Affiliation(s)
- Norah A Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, USA.
| | - Miriam T Levy
- Department of Gastroenterology and Liver, Liverpool Hospital, University of New South Wales, Sydney, New South Wales, Australia
| | - Ka Wang Cheung
- Department of Obstetrics and Gynaecology, Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong
| | - Gonzague Jourdain
- French National Research Institute for Sustainable Development (IRD), Marseille, France.,Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
24
|
Sarkar M, Brady CW, Fleckenstein J, Forde KA, Khungar V, Molleston JP, Afshar Y, Terrault NA. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73:318-365. [PMID: 32946672 DOI: 10.1002/hep.31559] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Monika Sarkar
- University of California, San Francisco, San Francisco, CA
| | | | | | | | | | - Jean P Molleston
- Indiana University and Riley Hospital for Children, Indianapolis, IN
| | - Yalda Afshar
- University of California, Los Angeles, Los Angeles, CA
| | - Norah A Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| |
Collapse
|
|
25
|
Yu W, Hao X, Li Y, Yang C, Li Y, He Z, Huang F. Vertical transmission of hepatitis E virus in pregnant rhesus macaques. Sci Rep 2020; 10:17517. [PMID: 33060782 PMCID: PMC7567892 DOI: 10.1038/s41598-020-74461-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 09/25/2020] [Indexed: 12/20/2022] Open
Abstract
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. HEV causes high mortality in pregnant women. Its infection during pregnancy usually leads to fulminant hepatic failure, spontaneous abortions, premature delivery, or stillbirth. Vertical transmission of HEV has been reported, but the pathogenesis during pregnancy remains largely elusive. Pregnant rhesus macaques were infected with HEV to explore the pathogenesis of genotype 4 HEV infection during pregnancy. Active HEV infections were established with shedding viruses in the feces and blood, and elevated liver enzymes. Notably, higher viral titers and longer durations of HEV infection were found in HEV-infected pregnant rhesus macaques than in non-pregnant macaques. Premature delivery and fetal death occurred in one of the HEV-infected pregnant rhesus macaques. HEV RNA was detected in the liver, spleen, kidneys, and intestines of the dead fetus. This result strongly indicated vertical HEV transmission from mother to fetus. Maternal-transferred antibodies were observed in one of the babies with poor protection. The expressions of interferon-stimulated genes (ISGs) related to HEV infection were completely different between pregnant and non-pregnant rhesus macaques. During pregnancy, impaired innate immune responses, reduced progesterone levels, and shifts in immune states may aggravate HEV infection and result in adverse pregnancy outcomes.
Collapse
Affiliation(s)
- Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China
| | - Xianhui Hao
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yi Li
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Chenchen Yang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Yunlong Li
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Zhanlong He
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China.
| | - Fen Huang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China.
| |
Collapse
|
|
26
|
Abstract
PURPOSE OF REVIEW Hepatitis E virus (HEV) has gained increased global recognition in recent years, particularly in developed countries. We summarized here a selection of the literature published since the 1st of June, 2017. RECENT FINDINGS Longitudinal studies are increasingly conducted in Europe, to determine trends in HEV prevalence. The spectrum of mammals infected with HEV and potentially capable to transmit it to humans has widened. New virological data on HEV repCon and pathogenicity have been reported and clinical features of HEV infections have been precised or newly described. Finally, there are some new data on the therapeutic management of HEV infections in various clinical settings. SUMMARY HEV emergence in developed countries appears to be based on improved diagnosis tools and increased awareness of clinicians that HEV transmission is essentially autochthonous and is a possible cause of life-threatening acute hepatitis, chronic hepatitis, cirrhosis, and extra-hepatic symptoms. In addition, the distribution of HEV strains evolves. Ribavirin remains to date the only specific treatment recommended for HEV infection, being efficient in the majority but not in all cases.
Collapse
|
|
27
|
Abstract
BACKGROUND Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission. MAIN BODY HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined. CONCLUSION This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.
Collapse
Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Xiaoxue Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China.
| |
Collapse
|
|
28
|
Li S, Liu J, Williams MA, Ling W, Sun K, Lu C, Gao Y, Waigi MG. Metabolism of 17β-estradiol by Novosphingobium sp. ES2-1 as probed via HRMS combined with 13C 3-labeling. JOURNAL OF HAZARDOUS MATERIALS 2020; 389:121875. [PMID: 31862352 DOI: 10.1016/j.jhazmat.2019.121875] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/09/2019] [Accepted: 12/09/2019] [Indexed: 06/10/2023]
Abstract
This study investigated the biodegradation and metabolic mechanisms of 17β-estradiol (E2) by Novosphingobium sp. ES2-1 isolated from the activated sludge in a domestic sewage treatment plant (STP). It could degrade 97.1% E2 (73.5 μmol/L) in 7 d with a biodegradation half-life of 1.29 d. E2 was initially converted to estrone (E1), then to 4-hydroxyestrone (4-OH-E1), before subsequent monooxygenation reactions cleaved 4-OH-E1 into a metabolite with long-chain ketones structure (metabolite P8). However, when 4-OH-E1 was cleaved through the 4,5-seco pathway, the resulting phenol ring cleavage product could randomly condense with NH3 to yield a pyridine derivative, accompanied by the uncertain loss of a carboxy group at C4 before the condensation. The derivative was further oxidized into the metabolites with both pyridine and long-chain ketones structure (metabolite N5) through a similar formation mechanism as for P8 performed. This research presents several novel metabolites and shows that E2 can be biodegraded into the metabolite with long-chain structure through three optional pathways, thereby reducing E2 contamination.
Collapse
Affiliation(s)
- Shunyao Li
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Juan Liu
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Mark A Williams
- School of Plant and Environmental Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, United States
| | - Wanting Ling
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Kai Sun
- Anhui Province Key Laboratory of Farmland Ecological Conservation and Pollution Prevention, School of Resources and Environment, Anhui Agricultural University, Hefei, 230036, China
| | - Chao Lu
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yanzheng Gao
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Michael Gatheru Waigi
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| |
Collapse
|
|
29
|
Li S, Liu J, Sun K, Yang Z, Ling W. Degradation of 17β-estradiol by Novosphingobium sp. ES2-1 in aqueous solution contaminated with tetracyclines. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 260:114063. [PMID: 32014750 DOI: 10.1016/j.envpol.2020.114063] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/15/2020] [Accepted: 01/22/2020] [Indexed: 06/10/2023]
Abstract
17β-estradiol (E2) often coexists with tetracyclines (TCs) in wastewater lagoons at intensive breeding farms, threatening the quality of surrounding water bodies. Microbial degradation is vital in E2 removal, but it is unclear how TCs affect E2 biodegradation. This primary study investigated the mechanisms of E2 degradation by Novosphingobium sp. ES2-1 in the presence of TCs and assessed the removal efficiency of E2 by strain ES2-1 in natural waters containing TCs. E2 biodegradation was unaffected at TCs concentrations below 0.1 mg L-1 yet significantly inhibited at TCs above 10 mg L-1. As elevation of TCs, E2 biodegradation rate constant decreased, and the biodegradation kinetics equation gradually deviated from the pseudo-first-order dynamics model. Importantly, the presence of TCs, especially at high-level concentrations, significantly hindered E2 ring-opening process but promoted the condensation of some phenolic ring-opening products with NH3, thereby increasing the abundance of pyridine derivatives, which were difficult to decompose over time. Additionally, strain ES2-1 could remove 52.1-100% of nature estrogens in TCs-contaminated natural waters within 7 d. Results revealed the mechanisms of TCs in E2 biodegradation and the performance of a functional strain in estrogen removal in realistic TCs-contaminated aqueous solution.
Collapse
Affiliation(s)
- Shunyao Li
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Juan Liu
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Kai Sun
- Anhui Province Key Laboratory of Farmland Ecological Conservation and Pollution Prevention, School of Resources and Environment, Anhui Agricultural University, Hefei, 230036, China
| | - Zhiyao Yang
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wanting Ling
- Institute of Organic Contaminant Control and Soil Remediation, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China.
| |
Collapse
|
|
30
|
Immunobiological aspects of vaccines in pregnancy: Maternal perspective. MATERNAL IMMUNIZATION 2020. [PMCID: PMC7149477 DOI: 10.1016/b978-0-12-814582-1.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Immunization during pregnancy is an efficient strategy to protect both the mother and the newborn infant against infectious pathogens. Pregnant women have an increased susceptibility to severe infections caused by some pathogens, but the mechanisms involved remain poorly understood. Pregnancy is associated with dynamic changes in maternal immune system that are critical for tolerance of the fetus. These changes could also play an important role in shaping maternal immune components that are transferred to the newborn infant following natural infection or vaccination to prevent infectious diseases in early life. As the momentum for maternal immunization is growing, there is a need to increase our understanding of the immunobiology of maternal immunization in order to better prevent infectious diseases in the pregnant women and the young infant.
Collapse
|
|
31
|
Li M, Li S, He Q, Liang Z, Wang L, Wang Q, Wang L. Hepatitis E-related adverse pregnancy outcomes and their prevention by hepatitis E vaccine in a rabbit model. Emerg Microbes Infect 2019; 8:1066-1075. [PMID: 31339458 PMCID: PMC6711181 DOI: 10.1080/22221751.2019.1643260] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Hepatitis E virus (HEV) can lead to high mortality during pregnancy. This study was to investigate the adverse pregnancy outcomes caused by different HEV genotypes and their prevention by HEV 239 vaccine in rabbits. Forty-two female rabbits were randomly and equally divided into 7 groups (A-G). HEV 239 vaccine and a placebo were administered to groups E (10 μg×2), F (5 μg×2) and G (1 mL of PBS×2) before copulation. After pregnancy, 1 mL of 1.5×106 copies/mL rabbit HEV3 was inoculated to groups A, E, F and G, swine HEV4/human HEV3 to groups B/C, and group D was a negative control. Anti-HEV antibody, HEV RNA, and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels were monitored. Pregnant rabbits infected by HEV manifested HEV infection symptoms including fecal virus shedding, ALT/AST elevation, and histopathological changes, and adverse pregnancy outcomes. Immunized pregnant rabbits in groups E and F showed no HEV infection symptoms and adverse outcomes. The newborn rabbits delivered by pregnant rabbits with/without immunization showed without/with HEV infection symptoms. This study demonstrated that multiple genotypes of HEV infection can cause adverse outcomes and HEV 239 vaccine can prevent HEV-related adverse outcomes in pregnant rabbits.
Collapse
Affiliation(s)
- Manyu Li
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| | - Shuangshuang Li
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| | - Qiyu He
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| | - Zhaochao Liang
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| | - Lin Wang
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| | - Qianhui Wang
- b Department of Infectious Diseases , Taiyuan No. 3 Hospital, Taiyuan , Shanxi Province, People's Republic of China
| | - Ling Wang
- a Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center , Beijing , People's Republic of China
| |
Collapse
|
|
32
|
Hepatitis E in Pregnant Women and the Potential Use of HEV Vaccine to Prevent Maternal Infection and Mortality. CURRENT TROPICAL MEDICINE REPORTS 2019. [DOI: 10.1007/s40475-019-00193-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
|
|
33
|
Hartard C, Gantzer C, Bronowicki JP, Schvoerer E. Emerging hepatitis E virus compared with hepatitis A virus: A new sanitary challenge. Rev Med Virol 2019; 29:e2078. [PMID: 31456241 DOI: 10.1002/rmv.2078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022]
Abstract
Hepatitis A (HAV) and E (HEV) viruses are able to cause liver disease in humans. Among the five classical hepatotropic viruses, they are mainly transmitted via the fecal-oral route. Historically, many similarities have thus been described between them according to their incidence and their pathogenicity, especially in countries with poor sanitary conditions. However, recent advances have provided new insights, and the gap is widening between them. Indeed, while HAV infection incidence tends to decrease in developed countries along with public health improvement, HEV is currently considered as an underdiagnosed emerging pathogen. HEV autochthonous infections are increasingly observed and are mainly associated with zoonotic transmissions. Extra hepatic signs resulting in neurological or renal impairments have also been reported for HEV, as well as a chronic carrier state in immunocompromised patients, arguing in favor of differential pathogenesis between those two viruses. Recent molecular tools have allowed studies of viral genome variability and investigation of links between viral plasticity and clinical evolution. The identification of key functional mutations in viral genomes may improve the knowledge of their clinical impact and is analyzed in depth in the present review.
Collapse
Affiliation(s)
- Cédric Hartard
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Christophe Gantzer
- Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | | | - Evelyne Schvoerer
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| |
Collapse
|
|
34
|
Life cycle and morphogenesis of the hepatitis E virus. Emerg Microbes Infect 2018; 7:196. [PMID: 30498191 PMCID: PMC6265337 DOI: 10.1038/s41426-018-0198-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/01/2018] [Accepted: 11/05/2018] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus (HEV) is transmitted primarily via contaminated water and food by the fecal oral route and causes epidemics in developing countries. In industrialized countries, zoonotic transmission of HEV is prevalent. In addition, HEV is the major cause of acute hepatitis in healthy adults and can cause chronic hepatitis in immunocompromised patients, with pregnant HEV-infected women having increased mortality rates of approximately 25%. HEV was once an understudied and neglected virus. However, in recent years, the safety of blood products with respect to HEV has increasingly been considered to be a public health problem. The establishment of HEV infection models has enabled significant progress to be made in understanding its life cycle. HEV infects cells via a receptor (complex) that has yet to be identified. The HEV replication cycle is initiated immediately after the (+) stranded RNA genome is released into the cell cytosol. Subsequently, infectious viral particles are released by the ESCRT complex as quasi-enveloped viruses (eHEVs) into the serum, whereas feces and urine contain only nonenveloped infectious viral progeny. The uncoating of the viral envelope takes place in the biliary tract, resulting in the generation of a nonenveloped virus that is more resistant to environmental stress and possesses a higher infectivity than that of eHEV. This review summarizes the current knowledge regarding the HEV life cycle, viral morphogenesis, established model systems and vaccine development.
Collapse
|
|
35
|
Bochud M, Schäfer W, Roth NJ, Ros C. Characterization of a quasi-enveloped, fast replicating hepevirus from fish and its use as hepatitis E virus surrogate. J Virol Methods 2018; 263:111-119. [PMID: 30399394 DOI: 10.1016/j.jviromet.2018.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/23/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis E virus (HEV) is an emerging concern for the safety of plasma-derived medicinal products. The lack of an efficient cell culture system hampers the studies on HEV biology as well as validation studies to test the capacity of virus reduction steps to clear HEV. Hence, a surrogate hepevirus that can efficiently replicate in cell culture is needed. Cutthroat trout virus (CTV) is a non-pathogenic fish hepevirus, which can replicate in cell culture to high titers. Under interferon inhibition, CTV replication reached up to 5 × 107 genome equivalents per μL in 4-5 days. The intracellular CTV progeny was already lipid-associated, suggesting that the envelope is acquired from intracellular membranes. Transmission electron microscopy of purified quasi-enveloped virus revealed exosome-like structures with an average size of 40 nm, in contrast to 27-34 nm for the non-enveloped virus. The quasi-enveloped virus was significantly less infectious than the non-enveloped virus. Assays based on quantitative RT-PCR, immunofluorescence and immunocytochemistry were established to evaluate virus inactivation. Cold ethanol fractionation removed 3.0 log of CTV and pasteurization of human albumin inactivated more than 3.7 log to below the limit of detection. Similar to HEV, virus replication was promoted in the presence of 17β-estradiol, an effect that can contribute to the understanding of the exacerbated virulence of HEV in pregnant women. These results together reveal substantial similarities between the human and fish HEV and validate CTV as a practical virus model to use in some applications for evaluating the HEV reduction capacity of biological manufacturing process steps.
Collapse
Affiliation(s)
- Maëlle Bochud
- Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
| | - Wolfram Schäfer
- CSL Behring GmbH, Emil-von-Behring-Strasse 76, 35041, Marburg, Germany
| | - Nathan J Roth
- CSL Behring AG, Wankdorfstrasse 10, 3000, Bern 22, Switzerland
| | - Carlos Ros
- Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
| |
Collapse
|