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Winkler CW, Woods TA, Carmody AB, Taylor KG, LaCasse R, Scott D, Hanley PW, Lovaglio J, Peterson KE. Age dependent susceptibility and immune responses to La Crosse virus infection in non-human primates. Sci Rep 2025; 15:16628. [PMID: 40360698 PMCID: PMC12075599 DOI: 10.1038/s41598-025-01285-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
La Crosse virus (LACV) is a primary cause of pediatric viral encephalitis in the United States but rarely causes disease in adults. We tested whether cynomolgus macaques displayed a similar age-dependent susceptibility to LACV. Immune responses from naïve or LACV infected weanling (9-15 months), juvenile (19-23 months) or adult (> 6 years) animals were measured and infected animals were monitored for disease. Naïve weanling animals had fewer dendritic cells in their blood and weaker induction of IFN-stimulated genes (ISG) and chemokines when PBMCs were stimulated in vitro. While no infected animals developed disease, the weaker innate response in naive weanlings correlated with increased viral RNA in plasma from 2 of 3 infected weanlings out to 7 days post infection (dpi). Activated CD8+ T cells and neutralizing antibody proportions were similar amongst all ages. However, CD4+ T cells proportions were increased in young animals relative to adults. This suggests the CD4+ adaptive response in young animals may be bolstering an initially weak innate response to clear virus. Finally, because macaques were resistant to disease, we infected 3 common marmosets intranasally with LACV. Marmoset were selected due to their susceptibility to viral encephalitis. Although no animals showed disease signs, one animal had evidence of infection in the nasal mucosa out to 23 days with associated vacuolization, edema and immune cell infiltration.
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Affiliation(s)
- Clayton W Winkler
- Laboratory of Neurological Infections and Immunity, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, 903 S. 4th St., Hamilton, MT, 59840, USA.
| | - Tyson A Woods
- Laboratory of Neurological Infections and Immunity, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, 903 S. 4th St., Hamilton, MT, 59840, USA
| | - Aaron B Carmody
- Research Technologies Branch, Rocky Mountain Laboratories, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Katherine G Taylor
- Laboratory of Neurological Infections and Immunity, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, 903 S. 4th St., Hamilton, MT, 59840, USA
| | - Rachel LaCasse
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Dana Scott
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Patrick W Hanley
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Jamie Lovaglio
- Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Karin E Peterson
- Laboratory of Neurological Infections and Immunity, Department of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, 903 S. 4th St., Hamilton, MT, 59840, USA
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2
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Ding Z, Wang L, Sun J, Zheng L, Tang Y, Tang H. Hepatocellular carcinoma: pathogenesis, molecular mechanisms, and treatment advances. Front Oncol 2025; 15:1526206. [PMID: 40265012 PMCID: PMC12011620 DOI: 10.3389/fonc.2025.1526206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.
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Affiliation(s)
- Zhixian Ding
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lusheng Wang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Jiting Sun
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lijie Zheng
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Yu Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Heng Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
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3
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Colasanti O, Yu H, Lohmann V, Shin EC. Redefining the immune landscape of hepatitis A virus infection. Exp Mol Med 2025; 57:714-723. [PMID: 40175697 PMCID: PMC12046051 DOI: 10.1038/s12276-025-01431-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/07/2025] [Accepted: 01/17/2025] [Indexed: 04/04/2025] Open
Abstract
Despite the development of effective vaccines against hepatitis A virus (HAV) infection, outbreaks of acute hepatitis A still occur globally, such that HAV remains a major cause of acute viral hepatitis. Most patients with acute hepatitis A recover spontaneously; however, some adult cases result in acute liver failure due to immune-mediated liver damage. Previous studies suggested that HAV evades the innate immune response through strong counteractive mechanisms, and that HAV-specific CD8+ T cells contribute to liver damage in patients with acute hepatitis A. However, recent research findings have led to revisions of old hypotheses. Here we will describe the most current knowledge regarding the innate immune response to HAV and the HAV-mediated counteractions against innate immune responses. Additionally, we will discuss the roles of various types of T cells in viral clearance and liver injury in patients with acute hepatitis A.
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Affiliation(s)
- Ombretta Colasanti
- Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, Center for Integrative Infectious Disease Research, Heidelberg, Germany
| | - Hosun Yu
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Volker Lohmann
- Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, Center for Integrative Infectious Disease Research, Heidelberg, Germany.
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science, Daejeon, Republic of Korea.
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4
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Baig MMFA, Wong LY, Wu H. Development of mRNA nano-vaccines for COVID-19 prevention and its biochemical interactions with various disease conditions and age groups. J Drug Target 2024; 32:21-32. [PMID: 38010097 DOI: 10.1080/1061186x.2023.2288996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 11/18/2023] [Indexed: 11/29/2023]
Abstract
This review has focused on the development of mRNA nano-vaccine and the biochemical interactions of anti-COVID-19 mRNA vaccines with various disease conditions and age groups. It studied five major groups of individuals with different disease conditions and ages, including allergic background, infarction background, adolescent, and adult (youngsters), pregnant women, and elderly. All five groups had been reported to have background-related adverse effects. Allergic background individuals were observed to have higher chances of experiencing allergic reactions and even anaphylaxis. Individuals with an infarction background had a higher risk of vaccine-induced diseases, e.g. pneumonitis and interstitial lung diseases. Pregnant women were seen to suffer from obstetric and gynecological adverse effects after receiving vaccinations. However, interestingly, the elderly individuals (> 65 years old) had experienced milder and less frequent adverse effects compared to the adolescent (<19 and >9 years old) and young adulthood (19-39 years old), or middle adulthood (40-59 years old) age groups, while middle to late adolescent (14-17 years old) was the riskiest age group to vaccine-induced cardiovascular manifestations.
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Affiliation(s)
- Mirza Muhammad Faran Ashraf Baig
- Department of Chemistry and the Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Lok Yin Wong
- Department of Chemistry and the Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Hongkai Wu
- Department of Chemistry and the Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration, The Hong Kong University of Science and Technology, Hong Kong, China
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5
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Hsiung KC, Chiang HJ, Reinig S, Shih SR. Vaccine Strategies Against RNA Viruses: Current Advances and Future Directions. Vaccines (Basel) 2024; 12:1345. [PMID: 39772007 PMCID: PMC11679499 DOI: 10.3390/vaccines12121345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
The development of vaccines against RNA viruses has undergone a rapid evolution in recent years, particularly driven by the COVID-19 pandemic. This review examines the key roles that RNA viruses, with their high mutation rates and zoonotic potential, play in fostering vaccine innovation. We also discuss both traditional and modern vaccine platforms and the impact of new technologies, such as artificial intelligence, on optimizing immunization strategies. This review evaluates various vaccine platforms, ranging from traditional approaches (inactivated and live-attenuated vaccines) to modern technologies (subunit vaccines, viral and bacterial vectors, nucleic acid vaccines such as mRNA and DNA, and phage-like particle vaccines). To illustrate these platforms' practical applications, we present case studies of vaccines developed for RNA viruses such as SARS-CoV-2, influenza, Zika, and dengue. Additionally, we assess the role of artificial intelligence in predicting viral mutations and enhancing vaccine design. The case studies underscore the successful application of RNA-based vaccines, particularly in the fight against COVID-19, which has saved millions of lives. Current clinical trials for influenza, Zika, and dengue vaccines continue to show promise, highlighting the growing efficacy and adaptability of these platforms. Furthermore, artificial intelligence is driving improvements in vaccine candidate optimization and providing predictive models for viral evolution, enhancing our ability to respond to future outbreaks. Advances in vaccine technology, such as the success of mRNA vaccines against SARS-CoV-2, highlight the potential of nucleic acid platforms in combating RNA viruses. Ongoing trials for influenza, Zika, and dengue demonstrate platform adaptability, while artificial intelligence enhances vaccine design by predicting viral mutations. Integrating these innovations with the One Health approach, which unites human, animal, and environmental health, is essential for strengthening global preparedness against future RNA virus threats.
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Affiliation(s)
- Kuei-Ching Hsiung
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (K.-C.H.); (H.-J.C.); (S.R.)
| | - Huan-Jung Chiang
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (K.-C.H.); (H.-J.C.); (S.R.)
- Graduate Institute of Biomedical Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Sebastian Reinig
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (K.-C.H.); (H.-J.C.); (S.R.)
| | - Shin-Ru Shih
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (K.-C.H.); (H.-J.C.); (S.R.)
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medical Biotechnology & Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Research Center for Chinese Herbal Medicine, Research Center for Food & Cosmetic Safety, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science & Technology, Taoyuan 33303, Taiwan
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6
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Yosri M, Dokhan M, Aboagye E, Al Moussawy M, Abdelsamed HA. Mechanisms governing bystander activation of T cells. Front Immunol 2024; 15:1465889. [PMID: 39669576 PMCID: PMC11635090 DOI: 10.3389/fimmu.2024.1465889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/31/2024] [Indexed: 12/14/2024] Open
Abstract
The immune system is endowed with the capacity to distinguish between self and non-self, so-called immune tolerance or "consciousness of the immune system." This type of awareness is designed to achieve host protection by eliminating cells expressing a wide range of non-self antigens including microbial-derived peptides. Such a successful immune response is associated with the secretion of a whole spectrum of soluble mediators, e.g., cytokines and chemokines, which not only contribute to the clearance of infected host cells but also activate T cells that are not specific to the original cognate antigen. This kind of non-specific T-cell activation is called "bystander activation." Although it is well-established that this phenomenon is cytokine-dependent, there is evidence in the literature showing the involvement of peptide/MHC recognition depending on the type of T-cell subset (naive vs. memory). Here, we will summarize our current understanding of the mechanism(s) of bystander T-cell activation as well as its biological significance in a wide range of diseases including microbial infections, cancer, auto- and alloimmunity, and chronic inflammatory diseases such as atherosclerosis.
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Affiliation(s)
- Mohammed Yosri
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Mohamed Dokhan
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Elizabeth Aboagye
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Mouhamad Al Moussawy
- Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Hossam A. Abdelsamed
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
- Department of Physiology, Augusta University, Augusta, GA, United States
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7
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Bela-Ong DB, Thompson KD, Kim HJ, Park SB, Jung TS. CD4 + T lymphocyte responses to viruses and virus-relevant stimuli in teleost fish. FISH & SHELLFISH IMMUNOLOGY 2023; 142:109007. [PMID: 37625734 DOI: 10.1016/j.fsi.2023.109007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/31/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023]
Abstract
Fish diseases caused by viruses are a major threat to aquaculture. Development of disease protection strategies for sustainable fish aquaculture requires a better understanding of the immune mechanisms involved in antiviral defence. The innate and adaptive arms of the vertebrate immune system collaborate to mount an effective defence against viral pathogens. The T lymphocyte components of the adaptive immune system, comprising two major classes (helper T, Th or CD4+ and cytotoxic T lymphocytes, CTLs or CD8+ T cells), are responsible for cell-mediated immune responses. In particular, CD4+ T cells and their different subsets orchestrate the actions of various other immune cells during immune responses, making CD4+ T cells central drivers of responses to pathogens and vaccines. CD4+ T cells are also present in teleost fish. Here we review the literature that reported the use of antibodies against CD4 in a few teleost fish species and transcription profiling of Th cell-relevant genes in the context of viral infections and virus-relevant immunomodulation. Studies reveal massive CD4+ T cell proliferation and expression of key cytokines, transcription factors, and effector molecules that evoke mammalian Th cell responses. We also discuss gaps in the current understanding and evaluation of teleost CD4+ T cell responses and how development and application of novel tools and approaches to interrogate such responses could bridge these gaps. A greater understanding of fish Th cell responses will further illuminate the evolution of vertebrate adaptive immunity, inform strategies to address viral infections in aquaculture, and could further foster fish as model organisms.
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Affiliation(s)
- Dennis Berbulla Bela-Ong
- Laboratory of Aquatic Animal Diseases, Research Institute of Natural Science, College of Veterinary Medicine, Gyeongsang National University, 501-201, 501 Jinju-daero, Jinju-si, Gyeongsangnam-do, 52828, Republic of Korea.
| | - Kim D Thompson
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, EH26 0PZ, Scotland, United Kingdom
| | - Hyoung Jun Kim
- WOAH Reference Laboratory for VHS, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Seong Bin Park
- Coastal Research and Extension Center, Mississippi State University, Pascagula, MS, 39567, USA
| | - Tae Sung Jung
- Laboratory of Aquatic Animal Diseases, Research Institute of Natural Science, College of Veterinary Medicine, Gyeongsang National University, 501-201, 501 Jinju-daero, Jinju-si, Gyeongsangnam-do, 52828, Republic of Korea.
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8
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Van Damme P, Pintó RM, Feng Z, Cui F, Gentile A, Shouval D. Hepatitis A virus infection. Nat Rev Dis Primers 2023; 9:51. [PMID: 37770459 DOI: 10.1038/s41572-023-00461-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 09/30/2023]
Abstract
Hepatitis A is a vaccine-preventable infection caused by the hepatitis A virus (HAV). Over 150 million new infections of hepatitis A occur annually. HAV causes an acute inflammatory reaction in the liver that usually resolves spontaneously without chronic sequelae. However, up to 20% of patients experience a prolonged or relapsed course and <1% experience acute liver failure. Host factors, such as immunological status, age, pregnancy and underlying hepatic diseases, can affect the severity of disease. Anti-HAV IgG antibodies produced in response to HAV infection persist for life and protect against re-infection; vaccine-induced antibodies against hepatitis A confer long-term protection. The WHO recommends vaccination for individuals at higher risk of infection and/or severe disease in countries with very low and low hepatitis A virus endemicity, and universal childhood vaccination in intermediate endemicity countries. To date, >25 countries worldwide have implemented such programmes, resulting in a reduction in the incidence of HAV infection. Improving hygiene and sanitation, rapid identification of outbreaks and fast and accurate intervention in outbreak control are essential to reducing HAV transmission.
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Affiliation(s)
- Pierre Van Damme
- Centre for the Evaluation of Vaccination, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
| | - Rosa M Pintó
- Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Zongdi Feng
- Centre for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Fuqiang Cui
- Department of Laboratorial Science and Technology & Vaccine Research Center, School of Public Health, Peking University, Beijing, People's Republic of China
| | - Angela Gentile
- Department of Epidemiology, Hospital de Niños Ricardo Gutierrez, University of Buenos Aires, Buenos Aires, Argentina
| | - Daniel Shouval
- Institute of Hepatology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
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9
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Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment. Vaccines (Basel) 2023; 11:681. [PMID: 36992265 PMCID: PMC10056334 DOI: 10.3390/vaccines11030681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.
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Affiliation(s)
| | | | - Eva Billerbeck
- Division of Hepatology, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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10
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Sun L, Feng H, Misumi I, Shirasaki T, Hensley L, González-López O, Shiota I, Chou WC, Ting JPY, Cullen JM, Cowley DO, Whitmire JK, Lemon SM. Viral protease cleavage of MAVS in genetically modified mice with hepatitis A virus infection. J Hepatol 2023; 78:271-280. [PMID: 36152761 DOI: 10.1016/j.jhep.2022.09.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/17/2022] [Accepted: 09/14/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Consistent with its relatively narrow host species range, hepatitis A virus (HAV) cannot infect C57BL/6 mice. However, in Mavs-/- mice with genetic deficiency of the innate immune signaling adaptor MAVS, HAV replicates robustly in the absence of disease. The HAV 3ABC protease cleaves MAVS in human cells, thereby disrupting virus-induced IFN responses, but it cannot cleave murine MAVS (mMAVS) due to sequence differences at the site of scission. Here, we sought to elucidate the role of 3ABC MAVS cleavage in determining HAV pathogenesis and host species range. METHODS Using CRISPR/Cas9 gene editing, we established two independent lineages of C57BL/6 mice with knock-in mutations altering two amino acids in mMAVS ('mMAVS-VS'), rendering it susceptible to 3ABC cleavage without loss of signaling function. We challenged homozygous Mavsvs/vs mice with HAV, and compared infection outcomes with C57BL/6 and genetically deficient Mavs-/- mice. RESULTS The humanized murine mMAVS-VS protein was cleaved as efficiently as human MAVS when co-expressed with 3ABC in Huh-7 cells. In embyronic fibroblasts from Mavsvs/vs mice, mMAVS-VS was cleaved by ectopically expressed 3ABC, significantly disrupting Sendai virus-induced IFN responses. However, in contrast to Mavs-/- mice with genetic MAVS deficiency, HAV failed to establish infection in Mavsvs/vs mice, even with additional genetic knockout of Trif or Irf1. Nonetheless, when crossed with permissive Ifnar1-/- mice lacking type I IFN receptors, Mavsvs/vsIfnar1-/- mice demonstrated enhanced viral replication coupled with significant reductions in serum alanine aminotransferase, hepatocellular apoptosis, and intrahepatic inflammatory cell infiltrates compared with Ifnar1-/- mice. CONCLUSIONS MAVS cleavage by 3ABC boosts viral replication and disrupts disease pathogenesis, but it is not by itself sufficient to break the host-species barrier to HAV infection in mice. IMPACT AND IMPLICATIONS The limited host range of human hepatitis viruses could be explained by species-specific viral strategies that disrupt innate immune responses. Both hepatitis A virus (HAV) and hepatitis C virus express viral proteases that cleave the innate immune adaptor protein MAVS, in human but not mouse cells. However, the impact of this immune evasion strategy has never been assessed in vivo. Here we show that HAV 3ABC protease cleavage of MAVS enhances viral replication and lessens liver inflammation in mice lacking interferon receptors, but that it is insufficient by itself to overcome the cross-species barrier to infection in mice. These results enhance our understanding of how hepatitis viruses interact with the host and their impact on innate immune responses.
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Affiliation(s)
- Lu Sun
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Hui Feng
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Ichiro Misumi
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - Takayoshi Shirasaki
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Lucinda Hensley
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Olga González-López
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Itoe Shiota
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - Wei-Chun Chou
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - John M Cullen
- College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, USA
| | - Dale O Cowley
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA; Animal Models Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Jason K Whitmire
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA; Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Stanley M Lemon
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
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11
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Shiota T, Matsuda M, Zheng X, Nagata N, Ishii K, Suzuki R, Muramatsu M, Takimoto K, Hanaki KI, Lemon SM, McGivern DR, Hirai-Yuki A. Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A in Ifnar1-/- Mice. J Virol 2022; 96:e0149622. [PMID: 36354341 PMCID: PMC9749467 DOI: 10.1128/jvi.01496-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 10/22/2022] [Indexed: 11/12/2022] Open
Abstract
Although hepatitis A virus (HAV) is associated only with acute hepatitis in humans, HAV RNA persists within the liver for months following resolution of liver inflammation and cessation of fecal virus shedding in chimpanzees and murine models of hepatitis A. Here, we confirm striking differences in the kinetics of HAV RNA clearance from liver versus serum and feces in infected Ifnar1-/- mice and investigate the nature of viral RNA persisting in the liver following normalization of serum alanine aminotransferase (ALT) levels. Fecal shedding of virus produced in hepatocytes declined >3,000-fold between its peak at day 14 and day 126, whereas intrahepatic HAV RNA declined only 32-fold by day 154. Viral RNA was identified within hepatocytes 3 to 4 months after inoculation and was associated with membranes, banding between 1.07 and 1.14 g/cm3 in isopycnic iodixanol gradients. Gradient fractions containing HAV RNA demonstrated no infectivity when inoculated into naive mice but contained neutralizing anti-HAV antibody. Depleting CD4+ or CD8+ T cells at this late point in infection had no effect on viral RNA abundance in the liver, whereas clodronate-liposome depletion of macrophages between days 110 and 120 postinoculation resulted in a striking recrudescence of fecal virus shedding and the reappearance of viral RNA in serum coupled with reductions in intra-hepatic Ifnγ, Tnfα, Ccl5, and other chemokine transcripts. Our data suggest that replication-competent HAV RNA persists for months within the liver in the presence of neutralizing antibody following resolution of acute hepatitis in Ifnar1-/- mice and that macrophages play a key role in viral control late in infection. IMPORTANCE HAV RNA persists in the liver of infected chimpanzees and interferon receptor-deficient Ifnar1-/- mice for many months after neutralizing antibodies appear, virus has been cleared from the blood, and fecal virus shedding has terminated. Here, we show this viral RNA is located within hepatocytes and that the depletion of macrophages months after the resolution of hepatic inflammation restores fecal virus shedding and circulating viral RNA. Our study identifies an important role for macrophages in virus control following resolution of acute hepatitis A in Ifnar1-/- mice and may have relevance to relapsing hepatitis A in humans.
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Affiliation(s)
- Tomoyuki Shiota
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Mami Matsuda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Xin Zheng
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Noriyo Nagata
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuhiro Takimoto
- Management Department of Biosafety, Laboratory Animal and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ken-Ichi Hanaki
- Management Department of Biosafety, Laboratory Animal and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan
| | - Stanley M. Lemon
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - David R. McGivern
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Asuka Hirai-Yuki
- Management Department of Biosafety, Laboratory Animal and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan
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12
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Lemon SM. Hepatitis A: Current view of an ancient disease. J Hepatol 2022; 77:243-244. [PMID: 35513903 DOI: 10.1016/j.jhep.2021.09.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/09/2021] [Accepted: 09/19/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Stanley M Lemon
- Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, Department of Medicine, Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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13
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Wu S, Yi W, Gao Y, Deng W, Bi X, Lin Y, Yang L, Lu Y, Liu R, Chang M, Shen G, Hu L, Zhang L, Li M, Xie Y. Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection. Front Immunol 2022; 13:893512. [PMID: 35634301 PMCID: PMC9130599 DOI: 10.3389/fimmu.2022.893512] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/11/2022] [Indexed: 12/28/2022] Open
Abstract
It is considered that chronic hepatitis B patients have obtained functional cure if they get hepatitis B surface antigen (HBsAg) seroclearance after treatment. Serum HBsAg is produced by cccDNA that is extremely difficult to clear and dslDNA that is integrated with host chromosome. High HBsAg serum level leads to failure of host immune system, which makes it unable to produce effective antiviral response required for HBsAg seroclerance. Therefore, it is very difficult to achieve functional cure, and fewer than 1% of chronic hepatitis B patients are cured with antiviral treatment annually. Some chronic hepatitis B patients are coinfected with other chronic viral infections, such as HIV, HCV and HDV, which makes more difficult to cure. However, it is found that the probability of obtaining HBsAg seroclearance in patients with coinfection is higher than that in patients with HBV monoinfection, especially in patients with HBV/HIV coinfection who have an up to 36% of HBsAg 5-year-seroclerance rate. The mechanism of this interesting phenomenon is related to the functional reconstruction of immune system after antiretroviral therapy (ART). The quantity increase and function recovery of HBV specific T cells and B cells, and the higher level of cytokines and chemokines such as IP-10, GM-CSF, promote HBsAg seroclearance. This review summarizes recent studies on the immune factors that have influence on HBsAg seroconversion in the chronic hepatitis B patients with viral coinfection, which might provide new insights for the development of therapeutic approaches to partially restore the specific immune response to HBV and other viruses.
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Affiliation(s)
- Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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14
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Significance of bystander T cell activation in microbial infection. Nat Immunol 2022; 23:13-22. [PMID: 34354279 DOI: 10.1038/s41590-021-00985-3] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
During microbial infection, pre-existing memory CD8+ T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8+ T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8+ T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8+ T cells. In this Review, we describe the history of research on bystander CD8+ T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.
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15
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T cells protect against hepatitis A virus infection and limit infection-induced liver injury. J Hepatol 2021; 75:1323-1334. [PMID: 34331968 PMCID: PMC8604763 DOI: 10.1016/j.jhep.2021.07.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Hepatitis A virus (HAV) is a common cause of enterically transmitted viral hepatitis. In non-immune individuals, infection results in typically transient but occasionally fulminant and fatal inflammatory liver injury. Virus-specific T cell frequencies peak when liver damage is at its zenith, leading to the prevalent notion that T cells exacerbate liver disease, as suspected for other hepatotropic virus infections. However, the overall contribution of T cells to the control of HAV and the pathogenesis of hepatitis A is unclear and has been impeded by a historic lack of small animal models. METHODS Ifnar1-/- mice are highly permissive for HAV and develop pathogenesis that recapitulates many features of hepatitis A. Using this model, we identified HAV-specific CD8+ and CD4+ T cells by epitope mapping, and then used tetramers and functional assays to quantify T cells in the liver at multiple times after infection. We assessed the relationships between HAV-specific T cell frequency, viral RNA amounts, and liver pathogenesis. RESULTS A large population of virus-specific T cells accumulated within the livers of Ifnar1-/- mice during the first 1-2 weeks of infection and persisted over time. HAV replication was enhanced and liver disease exacerbated when mice were depleted of T cells. Conversely, immunization with a peptide vaccine increased virus-specific CD8+ T cell frequencies in the liver, reduced viral RNA abundance, and lessened liver injury. CONCLUSION These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health. LAY SUMMARY Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.
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Ishizaka A, Koga M, Mizutani T, Lim LA, Adachi E, Ikeuchi K, Ueda R, Aoyagi H, Tanaka S, Kiyono H, Matano T, Aizaki H, Yoshio S, Mita E, Muramatsu M, Kanto T, Tsutsumi T, Yotsuyanagi H. Prolonged Gut Dysbiosis and Fecal Excretion of Hepatitis A Virus in Patients Infected with Human Immunodeficiency Virus. Viruses 2021; 13:v13102101. [PMID: 34696531 PMCID: PMC8539651 DOI: 10.3390/v13102101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.
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Affiliation(s)
- Aya Ishizaka
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- Japan Foundation for AIDS Prevention, Tokyo 101-0064, Japan
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
| | - Taketoshi Mizutani
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- Correspondence: (T.M.); (H.Y.)
| | - Lay Ahyoung Lim
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Ryuta Ueda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Haruyo Aoyagi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; (S.T.); (E.M.)
| | - Hiroshi Kiyono
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (cMAV), Department of Medicine, University of California San Diego, San Diego, CA 92093, USA
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
- Department of AIDS Vaccine Development, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan; (S.Y.); (T.K.)
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; (S.T.); (E.M.)
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan; (S.Y.); (T.K.)
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
- Correspondence: (T.M.); (H.Y.)
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17
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Sun L, Li Y, Misumi I, González-López O, Hensley L, Cullen JM, McGivern DR, Matsuda M, Suzuki R, Sen GC, Hirai-Yuki A, Whitmire JK, Lemon SM. IRF3-mediated pathogenicity in a murine model of human hepatitis A. PLoS Pathog 2021; 17:e1009960. [PMID: 34591933 PMCID: PMC8509855 DOI: 10.1371/journal.ppat.1009960] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/12/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2’-5’ oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol. Hepatitis A is a common and potentially serious disease involving inflammation and liver cell death resulting from infection with the picornavirus, hepatitis A virus (HAV). The pathogenesis of the disease is incompletely understood. Here, we have profiled changes in the RNA transcriptome of livers from mice with various genetic deficiencies in the innate immune response to HAV. We show that the liver injury associated with HAV infection in these mice results from the induction of genes under transcriptional control of interferon regulatory factor 3 (IRF3). We use high-throughput RNA sequencing to identify sets of genes induced in mice with wild-type versus transcriptionally-incompetent IRF3, rule out roles for type III interferons and IFIT proteins in disease pathogenesis, and identify genes with intrahepatic expression correlating closely with HAV-mediated liver pathology.
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Affiliation(s)
- Lu Sun
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - You Li
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Ichiro Misumi
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Olga González-López
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Lucinda Hensley
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - John M. Cullen
- College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America
| | - David R. McGivern
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Mami Matsuda
- Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan
| | - Ganes C. Sen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Asuka Hirai-Yuki
- Management Department of Biosafety and Laboratory Animal, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan
| | - Jason K. Whitmire
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Stanley M. Lemon
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
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Bremer W, Blasczyk H, Yin X, Duron ES, Grakoui A, Feng Z, Walker C. Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques. J Hepatol 2021; 75:557-564. [PMID: 33961939 PMCID: PMC8603813 DOI: 10.1016/j.jhep.2021.04.036] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS HEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Herein, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans. METHODS Rhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV genotype (gt)3 isolate derived from a chronically infected human patient. HEV replication, alanine aminotransferase, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection. RESULTS HEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell-depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function. CONCLUSIONS Liver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated rhesus macaques, and a 1-week delay in HEV clearance in CD8+ T cell-depleted rhesus macaques, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection. LAY SUMMARY The hepatitis E virus (HEV) is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.
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Affiliation(s)
- William Bremer
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s, 700 Children’s Drive, Columbus, OH, USA
| | - Heather Blasczyk
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s, 700 Children’s Drive, Columbus, OH, USA
| | - Xin Yin
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s, 700 Children’s Drive, Columbus, OH, USA
| | - Eduardo Salinas Duron
- Division of Microbiology and Immunology, Emory Vaccine Center and Emory University School of Medicine, Atlanta, GA, USA
| | - Arash Grakoui
- Division of Microbiology and Immunology, Emory Vaccine Center and Emory University School of Medicine, Atlanta, GA, USA
| | - Zongdi Feng
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s, 700 Children’s Drive, Columbus, OH, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Christopher Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's, 700 Children's Drive, Columbus, OH, USA; Division of Microbiology and Immunology, Emory Vaccine Center and Emory University School of Medicine, Atlanta, GA, USA.
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19
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Wang M, Feng Z. Mechanisms of Hepatocellular Injury in Hepatitis A. Viruses 2021; 13:v13050861. [PMID: 34066709 PMCID: PMC8151331 DOI: 10.3390/v13050861] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.
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Affiliation(s)
- Minghang Wang
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - Zongdi Feng
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Correspondence:
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20
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Pintó RM, Pérez-Rodríguez FJ, Costafreda MI, Chavarria-Miró G, Guix S, Ribes E, Bosch A. Pathogenicity and virulence of hepatitis A virus. Virulence 2021; 12:1174-1185. [PMID: 33843464 PMCID: PMC8043188 DOI: 10.1080/21505594.2021.1910442] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatitis A is an acute infection of the liver, which is mostly asymptomatic in children and increases the severity with age. Although in most patients the infection resolves completely, in a few of them it may follow a prolonged or relapsed course or even a fulminant form. The reason for these different outcomes is unknown, but it is generally accepted that host factors such as the immunological status, age and the occurrence of underlaying hepatic diseases are the main determinants of the severity. However, it cannot be ruled out that some virus traits may also contribute to the severe clinical outcomes. In this review, we will analyze which genetic determinants of the virus may determine virulence, in the context of a paradigmatic virus in terms of its genomic, molecular, replicative, and evolutionary features.
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Affiliation(s)
- Rosa M Pintó
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Francisco-Javier Pérez-Rodríguez
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain.,Present Address: Division of Infectious Diseases, Laboratory of Virology, University of Geneva Hospitals, Geneva, Switzerland
| | - Maria-Isabel Costafreda
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Gemma Chavarria-Miró
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Susana Guix
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Enric Ribes
- Enteric Virus Laboratory, Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain
| | - Albert Bosch
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
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21
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Hastings KL, Green MD, Gao B, Ganey PE, Roth RA, Burleson GR. Beyond Metabolism: Role of the Immune System in Hepatic Toxicity. Int J Toxicol 2021; 39:151-164. [PMID: 32174281 DOI: 10.1177/1091581819898399] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The liver is primarily thought of as a metabolic organ; however, the liver is also an important mediator of immunological functions. Key perspectives on this emerging topic were presented in a symposium at the 2018 annual meeting of the American College of Toxicology entitled "Beyond metabolism: Role of the immune system in hepatic toxicity." Viral hepatitis is an important disease of the liver for which insufficient preventive vaccines exist. Host immune responses inadequately clear these viruses and often potentiate immunological inflammation that damages the liver. In addition, the liver is a key innate immune organ against bacterial infection. Hepatocytes and immune cells cooperatively control systemic and local bacterial infections. Conversely, bacterial infection can activate multiple types of immune cells and pathways to cause hepatocyte damage and liver injury. Finally, the immune system and specifically cytokines and drugs can interact in idiosyncratic drug-induced liver injury. This rare disease can result in a disease spectrum that ranges from mild to acute liver failure. The immune system plays a role in this disease spectrum.
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Affiliation(s)
| | | | - Bin Gao
- Laboratory of Liver Diseases, NIH, Bethesda, MD, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Gary R Burleson
- BRT-Burleson Research Technologies, Inc, Morrisville, NC, USA
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22
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Kervevan J, Chakrabarti LA. Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions. Int J Mol Sci 2021; 22:E523. [PMID: 33430234 PMCID: PMC7825705 DOI: 10.3390/ijms22020523] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 12/26/2022] Open
Abstract
CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.
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Affiliation(s)
- Jérôme Kervevan
- Control of Chronic Viral Infections Group (CIVIC), Virus and Immunity Unit, Institut Pasteur, 75724 Paris, France;
- CNRS UMR, 3569 Paris, France
| | - Lisa A. Chakrabarti
- Control of Chronic Viral Infections Group (CIVIC), Virus and Immunity Unit, Institut Pasteur, 75724 Paris, France;
- CNRS UMR, 3569 Paris, France
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23
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The activation of bystander CD8 + T cells and their roles in viral infection. Exp Mol Med 2019; 51:1-9. [PMID: 31827070 PMCID: PMC6906361 DOI: 10.1038/s12276-019-0316-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/09/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
During viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as "bystander activation." Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.
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24
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Koga M, Lim LA, Ogishi M, Satoh H, Kikuchi T, Adachi E, Sugiyama R, Kiyohara T, Suzuki R, Muramatsu M, Koibuchi T, Tsutsumi T, Yotsuyanagi H. Comparison of the Clinical Features of Hepatitis A in People Living with HIV between Pandemics in 1999-2000 and 2017-2018 in the Metropolitan Area of Japan. Jpn J Infect Dis 2019; 73:89-95. [PMID: 31666497 DOI: 10.7883/yoken.jjid.2019.275] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Since 2017, hepatitis A virus (HAV) infection has been an epidemic among men who have sex with men (MSM) in Japan. We have come across 11 MSM patients with hepatitis A who were also infected with HIV. In 1999-2000, we came across 5 HIV-infected patients with hepatitis A. Since the conditions of current HIV-infected patients have changed owing to the recent progress in anti-HIV therapies, we compared clinical features of hepatitis A between patients in 2017-2018 and those in 1999-2000. By comparing the background characteristics of the patients, we found that the CD4/CD8 ratio was significantly higher in the 2017-2018 group. After the onset of hepatitis, peak levels of hepatic transaminases were found to be higher in the 2017-2018 group, suggesting severe hepatocellular damage. In contrast, neither the peak level of total bilirubin nor the nadir of prothrombin time was significantly different among the 2 groups. We also analyzed the HAV genome derived from some of the recently infected patients, and found that the HAV strains were almost the same among these patients; slight differences were observed from the previously identified strain. Thus, we concluded that the recovery of immunity by recent anti-HIV therapies may result in more severe hepatocellular damages and differences in clinical features.
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Affiliation(s)
- Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Lay Ahyoung Lim
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Masato Ogishi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Hidenori Satoh
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Tadashi Kikuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Ryuichi Sugiyama
- Department of Virology II, National Institute of Infectious Diseases
| | - Tomoko Kiyohara
- Department of Virology II, National Institute of Infectious Diseases
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases
| | | | - Tomohiko Koibuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo.,Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
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25
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Walker CM. Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a033472. [PMID: 29844218 DOI: 10.1101/cshperspect.a033472] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained. The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted.
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Affiliation(s)
- Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's, Columbus, Ohio 43004
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26
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Lemon SM, Walker CM. Hepatitis A Virus and Hepatitis E Virus: Emerging and Re-Emerging Enterically Transmitted Hepatitis Viruses. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031823. [PMID: 29735577 DOI: 10.1101/cshperspect.a031823] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Over the past two decades, progress in understanding human infections with hepatitis A virus (HAV) and hepatitis E virus (HEV) has been eclipsed by the priority of combating persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. During that time, the global burden of liver disease caused by enteric hepatitis viruses has not abated. Because of vaccines, hepatitis A has become increasingly a disease of adults instead of early childhood in many regions of the world, resulting in an age-related shift toward more severe disease. HEV has remained endemic in many developing countries, and in well-developed, economically advanced countries it is now recognized as a cause of chronic, progressive liver disease in individuals with compromised immunity. The goal of this collection of articles is to review recent progress and to shine a bright light on gaps in our understanding of how these viruses replicate, cause disease, interact with the liver and host immune system, and are transmitted, along with prospects for improved control in human populations. Renewed efforts to study and compare HAV and HEV biology in humans and animal models have high potential to enhance our understanding of host-pathogen balance in the liver, and may contribute ultimately to the control of other infectious diseases of the liver.
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Affiliation(s)
- Stanley M Lemon
- Departments of Medicine and Microbiology & Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University, Columbus, Ohio 43205
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27
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Feng Z, Lemon SM. Innate Immunity to Enteric Hepatitis Viruses. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a033464. [PMID: 29686040 DOI: 10.1101/cshperspect.a033464] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although hepatitis A virus (HAV) and hepatitis E virus (HEV) are both positive-strand RNA viruses that replicate in the cytoplasm of hepatocytes, there are important differences in the ways they induce and counteract host innate immune responses. HAV is remarkably stealthy because of its ability to evade and disrupt innate signaling pathways that lead to interferon production. In contrast, HEV does not block interferon production. Instead, it persists in the presence of an interferon response. These differences may provide insight into HEV persistence in immunocompromised patients, an emerging health problem in developed countries.
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Affiliation(s)
- Zongdi Feng
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio 43205
| | - Stanley M Lemon
- Departments of Medicine and Microbiology & Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599
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28
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Çomakli S, Özdemir S. Comparative Evaluation of the Immune Responses in Cattle Mammary Tissues Naturally Infected with Bovine Parainfluenza Virus Type 3 and Bovine Alphaherpesvirus-1. Pathogens 2019; 8:pathogens8010026. [PMID: 30823555 PMCID: PMC6470764 DOI: 10.3390/pathogens8010026] [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] [Received: 01/08/2019] [Revised: 02/11/2019] [Accepted: 02/20/2019] [Indexed: 12/21/2022] Open
Abstract
Bovine parainfluenza virus type 3 (BPIV-3) and Bovine alphaherpesvirus-1 (BoHV-1) lead to severe diseases in domesticated animals, such as Bovine, sheep, and goats. One of these diseases is mastitis, whose signs may not be observable in cases of viral infection due to the dominance of other clinical symptoms. This may lead to failure to predict viral agents in subclinical Bovine cases. Since viral infections have not been substantially investigated in mastitis studies, information about immune response to BPIV-3 and BoHV-1 infected Bovine mammary tissues may be inadequate. The present study aimed to determine the presence and prevalence of BPIV-3 and BoHV-1 agents in Bovine mammary tissues, and the immune response of such tissues against BPIV-3 and BoHV-1 infection. For this purpose, we first detected these viruses with qRT-PCR in mammary tissues. Then, we determined the expression profiles of interferon-γ (IFN-γ), CD4, and CD8 genes with qRT-PCR. Lastly, we performed immunohistochemistry staining to identify the presence of IFN-γ, CD4, and CD8 proteins in the mammary tissues. We found that 26, 16, and five of the 120 samples were BPI3-, BoHV1-, and BPIV-3 + BoHV-1 infected, respectively. Moreover, the gene expression levels of IFN-γ and CD4 were strongly up-regulated in the virus-infected tissues, whereas the CD8 gene expression level was only moderately up-regulated. Immunohistochemistry staining results were consistent with qRT-PCR results. Overall, our findings showed a high prevalence of BPIV-3 and BoHV-1 and indicated that cell-mediated immune response plays an important role against BPIV-3 and BoHV-1 infection in Bovine mammary tissues. Meanwhile, IFN-γ is an important cytokine for antiviral immunity against such infection.
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Affiliation(s)
- Selim Çomakli
- Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Yakutiye 25240, Erzurum, Turkey.
| | - Selçuk Özdemir
- Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, Yakutiye 25240, Erzurum, Turkey.
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29
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Lanford RE, Walker CM, Lemon SM. Nonhuman Primate Models of Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:a031815. [PMID: 29686041 PMCID: PMC6360867 DOI: 10.1101/cshperspect.a031815] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Although phylogenetically unrelated, human hepatitis viruses share an exclusive or near exclusive tropism for replication in differentiated hepatocytes. This narrow tissue tropism may contribute to the restriction of the host ranges of these viruses to relatively few host species, mostly nonhuman primates. Nonhuman primate models thus figure prominently in our current understanding of the replication and pathogenesis of these viruses, including the enterically transmitted hepatitis A virus (HAV) and hepatitis E virus (HEV), and have also played major roles in vaccine development. This review draws comparisons of HAV and HEV infection from studies conducted in nonhuman primates, and describes how such studies have contributed to our current understanding of the biology of these viruses.
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Affiliation(s)
- Robert E Lanford
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas 782227
| | - Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University, Columbus, Ohio 43205
| | - Stanley M Lemon
- Departments of Medicine and Microbiology & Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7030
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30
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Hirai-Yuki A, Whitmire JK, Joyce M, Tyrrell DL, Lemon SM. Murine Models of Hepatitis A Virus Infection. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031674. [PMID: 29661811 DOI: 10.1101/cshperspect.a031674] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mechanistic analyses of hepatitis A virus (HAV)-induced pathogenesis have long been thwarted by the lack of tractable small animal models that recapitulate disease observed in humans. Several approaches have shown success, including infection of chimeric mice with human liver cells. Other recent studies show that HAV can replicate to high titer in mice lacking expression of the type I interferon (IFN) receptor (IFN-α/β receptor) or mitochondrial antiviral signaling (MAVS) protein. Mice deficient in the IFN receptor show critical features of type A hepatitis in humans when challenged with human HAV, including histological evidence of liver damage, leukocyte infiltration, and the release of liver enzymes into blood. Acute pathogenesis is caused by MAVS-dependent signaling that leads to intrinsic apoptosis of hepatocytes.
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Affiliation(s)
- Asuka Hirai-Yuki
- Division of Experimental Animal Research, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
| | - Jason K Whitmire
- Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.,Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Michael Joyce
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton T6G 2E1, Canada.,Li Ka Shing Institute for Virology, University of Alberta, Edmonton T6G 2E1, Canada
| | - D Lorne Tyrrell
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton T6G 2E1, Canada.,Li Ka Shing Institute for Virology, University of Alberta, Edmonton T6G 2E1, Canada
| | - Stanley M Lemon
- Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, North Carolina 27599.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27517
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31
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Redundant Late Domain Functions of Tandem VP2 YPX 3L Motifs in Nonlytic Cellular Egress of Quasi-enveloped Hepatitis A Virus. J Virol 2018; 92:JVI.01308-18. [PMID: 30232181 DOI: 10.1128/jvi.01308-18] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/14/2018] [Indexed: 02/06/2023] Open
Abstract
The quasi-envelopment of hepatitis A virus (HAV) capsids in exosome-like virions (eHAV) is an important but incompletely understood aspect of the hepatovirus life cycle. This process is driven by recruitment of newly assembled capsids to endosomal vesicles into which they bud to form multivesicular bodies with intraluminal vesicles that are later released at the plasma membrane as eHAV. The endosomal sorting complexes required for transport (ESCRT) are key to this process, as is the ESCRT-III-associated protein, ALIX, which also contributes to membrane budding of conventional enveloped viruses. YPX1or3L late domains in the structural proteins of these viruses mediate interactions with ALIX, and two such domains exist in the HAV VP2 capsid protein. Mutational studies of these domains are confounded by the fact that the Tyr residues (important for interactions of YPX1or3L peptides with ALIX) are required for efficient capsid assembly. However, single Leu-to-Ala substitutions within either VP2 YPX3L motif (L1-A and L2-A mutants) were well tolerated, albeit associated with significantly reduced eHAV release. In contrast, simultaneous substitutions in both motifs (L1,2-A) eliminated virus release but did not inhibit assembly of infectious intracellular particles. Immunoprecipitation experiments suggested that the loss of eHAV release was associated with a loss of ALIX recruitment. Collectively, these data indicate that HAV YPX3L motifs function as redundant late domains during quasi-envelopment and viral release. Since these motifs present little solvent-accessible area in the crystal structure of the naked extracellular capsid, the capsid structure may be substantially different during quasi-envelopment.IMPORTANCE Nonlytic release of hepatitis A virus (HAV) as exosome-like quasi-enveloped virions is a unique but incompletely understood aspect of the hepatovirus life cycle. Several lines of evidence indicate that the host protein ALIX is essential for this process. Tandem YPX3L "late domains" in the VP2 capsid protein could be sites of interaction with ALIX, but they are not accessible on the surface of an X-ray model of the extracellular capsid, raising doubts about this putative late domain function. Here, we describe YPX3L domain mutants that assemble capsids normally but fail to bind ALIX and be secreted as quasi-enveloped eHAV. Our data support late domain function for the VP2 YPX3L motifs and raise questions about the structure of the HAV capsid prior to and following quasi-envelopment.
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32
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Shin EC, Jeong SH. Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a031708. [PMID: 29440324 DOI: 10.1101/cshperspect.a031708] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.
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Affiliation(s)
- Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seongnam, Gyeonggido 13620, Republic of Korea
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33
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Cao X, Xue YJ, Du JL, Xu Q, Yang XC, Zeng Y, Wang BB, Wang HZ, Liu J, Cai KZ, Ma ZR. Induction and Suppression of Innate Antiviral Responses by Hepatitis A Virus. Front Microbiol 2018; 9:1865. [PMID: 30174659 PMCID: PMC6107850 DOI: 10.3389/fmicb.2018.01865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 07/25/2018] [Indexed: 12/25/2022] Open
Abstract
Hepatitis A virus (HAV) belongs to the family Picornaviridae. It is the pathogen of acute viral hepatitis caused by fecal-oral transmission. RNA viruses are sensed by pathogen-associated pattern recognition receptors (PRRs) such as Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5). PRR activation leads to production of type 1 interferon (IFN-α/β), serving as the first line of defense against viruses. However, HAV has developed various strategies to compromise the innate immune system and promote viral propagation within the host cells. The long coevolution of HAV in hosts has prompted the development of effective immune antagonism strategies that actively fight against host antiviral responses. Proteases encoded by HAV can cleave the mitochondrial antiviral signaling protein (MAVS, also known as IPS-1, VISA, or Cardif), TIR domain- containing adaptor inducing IFN-β (TRIF, also known as TICAM-1) and nuclear factor-κB (NF-κB) essential modulator (NEMO), which are key adaptor proteins in RIG-I-like receptor (RLR), TLR3 and NF-κB signaling, respectively. In this mini-review, we summarize all the recent progress on the interaction between HAV and the host, especially focusing on how HAV abrogates the antiviral effects of the innate immune system.
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Affiliation(s)
- Xin Cao
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Yu-jia Xue
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Jiang-long Du
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Qiang Xu
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Xue-cai Yang
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Yan Zeng
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Bo-bo Wang
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Hai-zhen Wang
- Hebi Precision Medical Research Institute, People's Hospital of Hebi, Hebi, China
| | - Jing Liu
- Department of Medical OncologyPeople's Hospital of Hebi, Hebi, China
| | - Kui-zheng Cai
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
| | - Zhong-ren Ma
- College of Life Science and Engineering, Northwest Minzu University, Engineering & Technology Research Center for Animal Cell, Lanzhou, China
- Key Laboratory of Bioengineering & Biotechnology of State Ethnic Affairs Commission, Lanzhou, China
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Trujillo-Ochoa JL, Corral-Jara KF, Charles-Niño CL, Panduro A, Fierro NA. Conjugated Bilirubin Upregulates TIM-3 Expression on CD4 +CD25 + T Cells: Anti-Inflammatory Implications for Hepatitis A Virus Infection. Viral Immunol 2018; 31:223-232. [PMID: 29099687 DOI: 10.1089/vim.2017.0103] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bilirubin (BR), a metabolite with increased concentrations in plasma during viral hepatitis, has been recognized as a potential immune-modulator. We recently reported that conjugated BR (CB) augments regulatory T cell (Treg) suppressor activity during acute hepatitis A virus (HAV) infection. However, the mechanisms related to the effects of CB on Treg function in the course of hepatotropic viral diseases have not been elucidated. T cell immunoglobulin domain and mucin domain 3 (TIM-3), via its interactions with galectin-9 (GAL-9), is a receptor associated with enhanced Treg function. Thus, TIM-3 expression may be related to the crosstalk between CB and Tregs during HAV infection. Herein, in vitro treatment with high concentrations of CB upregulated TIM-3 expression on Tregs from healthy donors. CB treatment in vitro did not induce de novo Treg generation, and in vitro stimulation with TGF-β, which shows increased secretion during HAV infection, resulted in a trend toward increased TIM-3 expression on Tregs and CD4+ T lymphocytes (TLs) from healthy donors. Interestingly, an upregulation of TIM-3 expression on CD4+CD25+ T cells and an increase in the proportion of CD4+ TLs expressing GAL-9 were found in HAV-infected patients with abnormal CB values relative to healthy controls. In addition, a statistically significantly reduction in IL-17F production was observed after treatment of CD4+ TLs from healthy donors with high doses of CB in vitro. In summary, our results suggest that CB might regulate Treg activity via a TIM-3-mediated mechanism, ultimately leading to an anti-inflammatory hepatoprotective effect.
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Affiliation(s)
- Jorge L Trujillo-Ochoa
- 1 Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde," Guadalajara, México
- 2 Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, México
| | - Karla F Corral-Jara
- 1 Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde," Guadalajara, México
- 3 Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, México
| | - Claudia L Charles-Niño
- 4 Departamento de Microbiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, México
| | - Arturo Panduro
- 3 Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, México
- 5 Servicio de Biología Molecular, Hospital Civil of Guadalajara "Fray Antonio Alcalde," Guadalajara, México
| | - Nora A Fierro
- 1 Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde," Guadalajara, México
- 2 Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, México
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Boettler T, Thimme R. Lost in Inflammation: The Functional Conversion of Regulatory T Cells in Acute Hepatitis A Virus Infection. Gastroenterology 2018; 154:798-800. [PMID: 29427580 DOI: 10.1053/j.gastro.2018.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Tobias Boettler
- Department of Medicine II, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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36
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Kim J, Chang DY, Lee HW, Lee H, Kim JH, Sung PS, Kim KH, Hong SH, Kang W, Lee J, Shin SY, Yu HT, You S, Choi YS, Oh I, Lee DH, Lee DH, Jung MK, Suh KS, Hwang S, Kim W, Park SH, Kim HJ, Shin EC. Innate-like Cytotoxic Function of Bystander-Activated CD8 + T Cells Is Associated with Liver Injury in Acute Hepatitis A. Immunity 2018; 48:161-173.e5. [PMID: 29305140 DOI: 10.1016/j.immuni.2017.11.025] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/18/2017] [Accepted: 11/29/2017] [Indexed: 12/23/2022]
Abstract
Acute hepatitis A (AHA) involves severe CD8+ T cell-mediated liver injury. Here we showed during AHA, CD8+ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8+ T cells. TCR-independent activation of non-HAV-specific CD8+ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8+ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8+ T cells and the innate-like cytolytic activity of CD8+ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8+ T cells, a result with implications for acute viral diseases.
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Affiliation(s)
- Jihye Kim
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Dong-Yeop Chang
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
| | - Hoyoung Lee
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Jong Hoon Kim
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Pil Soo Sung
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Kyung Hwan Kim
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Seon-Hui Hong
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Wonseok Kang
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Jino Lee
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - So Youn Shin
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Hee Tae Yu
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Sooseong You
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Yoon Seok Choi
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Insoo Oh
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Dong Ho Lee
- Department of Surgery, College of Medicine, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon 34943, Republic of Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Min Kyung Jung
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Su-Hyung Park
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul 06973, Republic of Korea.
| | - Eui-Cheol Shin
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
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Lanford RE, Walker CM, Lemon SM. The Chimpanzee Model of Viral Hepatitis: Advances in Understanding the Immune Response and Treatment of Viral Hepatitis. ILAR J 2017; 58:172-189. [PMID: 29045731 PMCID: PMC5886334 DOI: 10.1093/ilar/ilx028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 08/04/2017] [Indexed: 12/18/2022] Open
Abstract
Chimpanzees (Pan troglodytes) have contributed to diverse fields of biomedical research due to their close genetic relationship to humans and in many instances due to the lack of any other animal model. This review focuses on the contributions of the chimpanzee model to research on hepatitis viruses where chimpanzees represented the only animal model (hepatitis B and C) or the most appropriate animal model (hepatitis A). Research with chimpanzees led to the development of vaccines for HAV and HBV that are used worldwide to protect hundreds of millions from these diseases and, where fully implemented, have provided immunity for entire generations. More recently, chimpanzee research was instrumental in the development of curative therapies for hepatitis C virus infections. Over a span of 40 years, this research would identify the causative agent of NonA,NonB hepatitis, validate the molecular tools for drug discovery, and provide safety and efficacy data on the therapies that now provide a rapid and complete cure of HCV chronic infections. Several cocktails of antivirals are FDA approved that eliminate the virus following 12 weeks of once-per-day oral therapy. This represents the first cure of a chronic viral disease and, once broadly implemented, will dramatically reduce the occurrence of cirrhosis and liver cancer. The recent contributions of chimpanzees to our current understanding of T cell immunity for HCV, development of novel therapeutics for HBV, and the biology of HAV are reviewed. Finally, a perspective is provided on the events leading to the cessation of the use of chimpanzees in research and the future of the chimpanzees previously used to bring about these amazing breakthroughs in human healthcare.
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Affiliation(s)
- Robert E Lanford
- Robert E. Lanford, PhD, is director at Southwest National Primate Research Center, Texas Biomedical Research Institute in San Antonio, Texas. Christopher M. Walker, PhD, is at the Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University in Columbus, Ohio. Stanley M. Lemon, MD, is at thea Department of Medicine, Division of Infectious Diseases; Lineberger Comprehensive Cancer Center; and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill in Chapel Hill, North Carolina.
| | - Christopher M Walker
- Robert E. Lanford, PhD, is director at Southwest National Primate Research Center, Texas Biomedical Research Institute in San Antonio, Texas. Christopher M. Walker, PhD, is at the Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University in Columbus, Ohio. Stanley M. Lemon, MD, is at thea Department of Medicine, Division of Infectious Diseases; Lineberger Comprehensive Cancer Center; and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill in Chapel Hill, North Carolina.
| | - Stanley M Lemon
- Robert E. Lanford, PhD, is director at Southwest National Primate Research Center, Texas Biomedical Research Institute in San Antonio, Texas. Christopher M. Walker, PhD, is at the Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University in Columbus, Ohio. Stanley M. Lemon, MD, is at thea Department of Medicine, Division of Infectious Diseases; Lineberger Comprehensive Cancer Center; and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill in Chapel Hill, North Carolina.
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38
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Mao S, Wang M, Ou X, Sun D, Cheng A, Zhu D, Chen S, Jia R, Liu M, Sun K, Yang Q, Wu Y, Zhao X, Chen X. Virologic and Immunologic Characteristics in Mature Ducks with Acute Duck Hepatitis A Virus 1 Infection. Front Immunol 2017; 8:1574. [PMID: 29201029 PMCID: PMC5696325 DOI: 10.3389/fimmu.2017.01574] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 11/02/2017] [Indexed: 12/16/2022] Open
Abstract
Duck hepatitis A virus 1 (DHAV-1) infection in mature ducks has previously been proposed as a small-animal model for human hepatitis A. However, basic research on the outcome of DHAV-1 infection in mature ducks is limited. Here, we examined the course of viremia, the characteristics of antibody responses, and the profiles of plasma cytokines in mature ducks infected with DHAV-1. During the course of infection, the viremia was detectable soon after infection and persisted for 196 days, however, the ducks presented as clinically asymptomatic. Specific and timely immunoglobulin G (IgG), IgM, and IgA1 responses were elicited. At the same time, extensive inhibition of viral replication was observed with increasing IgG concentration. With respect to pattern-recognition receptors, TLR-7 was mainly involved in triggering the innate defense against the DHAV-1 infection. In addition, plasma immune analytes were measured and were determined to have bidirectional roles in virus clearance. It was concluded that DHAV-1 spreads quickly in blood. The spontaneous clearance of DHAV-1 during asymptomatic infection in mature ducks depends on the cooperation of timely antibody responses and alert innate immune responses. Moreover, the delayed clearance may be associated with a weak interferon-γ-producing CD8+ T cell response. This study allows us to reveal the mechanism of clearance and persistence of DHAV-1 infection in mature ducks. We anticipate that it will provide a basis for future studies focused on defining the nature mechanisms involved in the clearance and persistence of human hepatitis virus.
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Affiliation(s)
- Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Di Sun
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Kunfeng Sun
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xinxin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyue Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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Lemon SM, Ott JJ, Van Damme P, Shouval D. Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention. J Hepatol 2017; 68:S0168-8278(17)32278-X. [PMID: 28887164 DOI: 10.1016/j.jhep.2017.08.034] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/30/2017] [Accepted: 08/30/2017] [Indexed: 02/08/2023]
Abstract
Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide prevalence and incidence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in the prevalence of HAV have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection, and review medical and public health aspects of immunisation and disease prevention.
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Affiliation(s)
- Stanley M Lemon
- Lineberger Comprehensive Cancer Center, and the Departments of Medicine and Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
| | - Jördis J Ott
- Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany.
| | - Pierre Van Damme
- Centre for the Evaluation of Vaccination, Vaccine & Infectious Disease Institute, Antwerp University, Antwerp, Belgium
| | - Daniel Shouval
- Liver Unit, Institute for Gastroenterology and Hepatology, Hadassah-Hebrew University Hospital, P.O.Box 12000, Jerusalem 91120, Israel
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40
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Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis. Int J Mol Sci 2017; 18:ijms18071517. [PMID: 28703774 PMCID: PMC5536007 DOI: 10.3390/ijms18071517] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/03/2017] [Accepted: 07/04/2017] [Indexed: 12/21/2022] Open
Abstract
Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.
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Fierro N, Gonzalez-Aldaco K, Roman S, Panduro A. The Immune System and Viral Hepatitis. LIVER PATHOPHYSIOLOGY 2017:129-139. [DOI: 10.1016/b978-0-12-804274-8.00009-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Melgaço JG, Soriani FM, Sucupira PHF, Pinheiro LA, Vieira YR, de Oliveira JM, Lewis-Ximenez LL, Araújo CCV, Pacheco-Moreira LF, Menezes GB, Cruz OG, Vitral CL, Pinto MA. Changes in cellular proliferation and plasma products are associated with liver failure. World J Hepatol 2016; 8:1370-1383. [PMID: 27917263 PMCID: PMC5114473 DOI: 10.4254/wjh.v8.i32.1370] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/03/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To study the differences in immune response and cytokine profile between acute liver failure and self-limited acute hepatitis.
METHODS Forty-six patients with self-limited acute hepatitis (AH), sixteen patients with acute liver failure (ALF), and twenty-two healthy subjects were involved in this study. The inflammatory and anti-inflammatory products in plasma samples were quantified using commercial enzyme-linked immunoassays and quantitative real-time PCR. The cellular immune responses were measured by proliferation assay using flow cytometry. The groups were divided into viral- and non-viral-induced self-limited AH and ALF. Thus, we worked with five groups: Hepatitis A virus (HAV)-induced self-limited acute hepatitis (HAV-AH), HAV-induced ALF (HAV-ALF), non-viral-induced self-limited acute hepatitis (non-viral AH), non-viral-induced acute liver failure (non-viral ALF), and healthy subjects (HC). Comparisons among HAV and non-viral-induced AH and ALF were performed.
RESULTS The levels of mitochondrial DNA (mtDNA) and the cytokines investigated [interleukin (IL)-6, IL-8, IL-10, interferon gamma, and tumor necrosis factor] were significantly increased in ALF patients, independently of etiology (P < 0.05). High plasma mtDNA and IL-10 were the best markers associated with ALF [mtDNA: OR = 320.5 (95%CI: 14.42-7123.33), P < 0.0001; and IL-10: OR = 18.8 (95%CI: 1.38-257.94), P = 0.028] and death [mtDNA: OR = 12.1 (95%CI: 2.57-57.07), P = 0.002; and IL-10: OR = 8.01 (95%CI: 1.26-50.97), P = 0.027]. In the cellular proliferation assay, NKbright, NKT and regulatory T cells (TReg) predominated in virus-specific stimulation in HAV-induced ALF patients with an anergic behavior in the cellular response to mitotic stimulation. Therefore, in non-viral-induced ALF, anergic behavior of activated T cells was not observed after mitotic stimulation, as expected and as described by the literature.
CONCLUSION mtDNA and IL-10 may be predictors of ALF and death. TReg cells are involved in immunological disturbance in HAV-induced ALF.
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Hirai-Yuki A, Hensley L, McGivern DR, González-López O, Das A, Feng H, Sun L, Wilson JE, Hu F, Feng Z, Lovell W, Misumi I, Ting JPY, Montgomery S, Cullen J, Whitmire JK, Lemon SM. MAVS-dependent host species range and pathogenicity of human hepatitis A virus. Science 2016; 353:1541-1545. [PMID: 27633528 PMCID: PMC5068972 DOI: 10.1126/science.aaf8325] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/02/2016] [Indexed: 12/24/2022]
Abstract
Hepatotropic viruses are important causes of human disease, but the intrahepatic immune response to hepatitis viruses is poorly understood because of a lack of tractable small- animal models. We describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly resulted from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver.
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Affiliation(s)
- Asuka Hirai-Yuki
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Lucinda Hensley
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - David R McGivern
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Medicine, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Olga González-López
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Anshuman Das
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Hui Feng
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Lu Sun
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Justin E Wilson
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Fengyu Hu
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Zongdi Feng
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA
| | - William Lovell
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Ichiro Misumi
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Stephanie Montgomery
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27517, USA
| | - John Cullen
- Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27607, USA
| | - Jason K Whitmire
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Genetics, University of North Carolina, Chapel Hill, NC 27517, USA
| | - Stanley M Lemon
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27517, USA. Department of Medicine, University of North Carolina, Chapel Hill, NC 27517, USA.
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Pachnio A, Ciaurriz M, Begum J, Lal N, Zuo J, Beggs A, Moss P. Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium. PLoS Pathog 2016; 12:e1005832. [PMID: 27606804 PMCID: PMC5015996 DOI: 10.1371/journal.ppat.1005832] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 07/28/2016] [Indexed: 12/24/2022] Open
Abstract
Cytomegalovirus (CMV) infection elicits a very strong and sustained intravascular T cell immune response which may contribute towards development of accelerated immune senescence and vascular disease in older people. Virus-specific CD8+ T cell responses have been investigated extensively through the use of HLA-peptide tetramers but much less is known regarding CMV-specific CD4+ T cells. We used a range of HLA class II-peptide tetramers to investigate the phenotypic and transcriptional profile of CMV-specific CD4+ T cells within healthy donors. We show that such cells comprise an average of 0.45% of the CD4+ T cell pool and can reach up to 24% in some individuals (range 0.01–24%). CMV-specific CD4+ T cells display a highly differentiated effector memory phenotype and express a range of cytokines, dominated by dual TNF-α and IFN-γ expression, although substantial populations which express IL-4 were seen in some donors. Microarray analysis and phenotypic expression revealed a profile of unique features. These include the expression of CX3CR1, which would direct cells towards fractalkine on activated endothelium, and the β2-adrenergic receptor, which could permit rapid response to stress. CMV-specific CD4+ T cells display an intense cytotoxic profile with high level expression of granzyme B and perforin, a pattern which increases further during aging. In addition CMV-specific CD4+ T cells demonstrate strong cytotoxic activity against antigen-loaded target cells when isolated directly ex vivo. PD-1 expression is present on 47% of cells but both the intensity and distribution of the inhibitory receptor is reduced in older people. These findings reveal the marked accumulation and unique phenotype of CMV-specific CD4+ T cells and indicate how such T cells may contribute to the vascular complications associated with CMV in older people. Cytomegalovirus (CMV) is a member of the herpesvirus family and most humans carry chronic CMV infection. This drives the development of large expansions of CD8+ CMV-specific T cells, which increase further during ageing. CMV infection is associated with vascular disease and increased risk of mortality in older people, which may be related to damage from this CMV-specific immune response. Here we used a set of novel reagents called HLA class II tetramers to make a detailed study of CMV-specific CD4+ T cells. We show that CMV-specific CD4+ T cells are found at remarkably high frequencies within blood, representing up to a quarter of all such white cells. In addition they demonstrate a range of unique features. Firstly they carry a chemokine receptor that directs the cells to activated endothelial cells within blood vessels. Secondly, they express epinephrine receptors which would allow them to respond rapidly to stress. Finally, these CD4+ T cells are unique as they are strongly cytotoxic and equipped with the ability to directly kill virally-infected cells. HLA class II tetramers therefore reveal a profile of unique features which provide insight into how CMV-specific CD4+ T cells may be involved in vascular immunopathology.
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Affiliation(s)
- Annette Pachnio
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
- * E-mail: (AP); (PM)
| | - Miriam Ciaurriz
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
- Oncohematology Research Group, Navarrabiomed-Fundación Miguel Servet, IDISNA (Navarra’s Health Research Institute), Pamplona, Spain
| | - Jusnara Begum
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
| | - Neeraj Lal
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
| | - Jianmin Zuo
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
| | - Andrew Beggs
- University of Birmingham, College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Edgbaston, Birmingham, United Kingdom
| | - Paul Moss
- University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom
- * E-mail: (AP); (PM)
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Abstract
Hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for most cases of viral hepatitis. Infection by each type of virus results in a different typical natural disease course and clinical outcome that are determined by virological and immunological factors. HCV tends to establish a chronic persistent infection, whereas HAV does not. HBV is effectively controlled in adults, although it persists for a lifetime after neonatal infection. In this Review, we discuss the similarities and differences in immune responses to and immunopathogenesis of HAV, HBV and HCV infections, which may explain the distinct courses and outcomes of each hepatitis virus infection.
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Gisa A, Suneetha PV, Behrendt P, Pischke S, Bremer B, Falk CS, Manns MP, Cornberg M, Wedemeyer H, Kraft ARM. Cross-genotype-specific T-cell responses in acute hepatitis E virus (HEV) infection. J Viral Hepat 2016; 23:305-15. [PMID: 26852892 DOI: 10.1111/jvh.12495] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 11/04/2015] [Indexed: 12/13/2022]
Abstract
Hepatitis E is an inflammatory liver disease caused by infection with the hepatitis E virus (HEV). In tropical regions, HEV is highly endemic and predominantly mediated by HEV genotypes 1 and 2 with >3 million symptomatic cases per year and around 70 000 deaths. In Europe and America, the zoonotic HEV genotypes 3 and 4 have been reported with continues increasing new infections per year. So far, little is known about T-cell responses during acute HEV genotype 3 infection. Therefore, we did a comprehensive study investigating HEV-specific T-cell responses using genotypes 3- and 1-specific overlapping peptides. Additional cytokines and chemokines were measured in the plasma. In four patients, longitudinal studies were performed. Broad functional HEV-specific CD4(+) and CD8(+) T-cell responses were detectable in patients acutely infected with HEV genotype 3. Elevated of pro- and anti-inflammatory cytokine levels during acute HEV infection correlated with ALT levels. Memory HEV-specific T-cell responses were detectable up to >1.5 years upon infection. Importantly, cross-genotype HEV-specific T-cell responses (between genotypes 1 and 3) were measurable in all investigated patients. In conclusion, we could show for the first time HEV-specific T-cell responses during and after acute HEV genotype 3 infection. Our data of cross-genotype HEV-specific T-cell responses might suggest a potential role in cross-genotype-specific protection between HEV genotypes 1 and 3.
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Affiliation(s)
- A Gisa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - P V Suneetha
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - P Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - S Pischke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,First Medical Center, University Hospital Hamburg-Eppendorf, Hannover, Germany
| | - B Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - C S Falk
- Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany
| | - M P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - M Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany
| | - A R M Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Grakoui A, Crispe IN. Presentation of hepatocellular antigens. Cell Mol Immunol 2016; 13:293-300. [PMID: 26924525 PMCID: PMC4856799 DOI: 10.1038/cmi.2015.109] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/24/2015] [Accepted: 11/25/2015] [Indexed: 12/31/2022] Open
Abstract
The liver is an organ in which antigen-specific T-cell responses manifest a bias toward immune tolerance. This is clearly seen in the rejection of allogeneic liver transplants, and multiple other phenomena suggest that this effect is more general. These include tolerance toward antigens introduced via the portal vein, immune failure to several hepatotropic viruses, the lack of natural liver-stage immunity to malaria parasites, and the frequent metastasis of cancers to the liver. Here we review the mechanisms by which T cells engage with hepatocellular antigens, the context in which such encounters occur, and the mechanisms that act to suppress a full T-cell response. While many mechanisms play a role, we will argue that two important processes are the constraints on the cross-presentation of hepatocellular antigens, and the induction of negative feedback inhibition driven by interferons. The constant exposure of the liver to microbial products from the intestine may drive innate immunity, rendering the local environment unfavorable for specific T-cell responses through this mechanism. Nevertheless, tolerance toward hepatocellular antigens is not monolithic and under specific circumstances allows both effective immunity and immunopathology.
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Affiliation(s)
- Arash Grakoui
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and Yerkes National Primate Research Center, Atlanta, GA, USA
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Corral-Jara KF, Trujillo-Ochoa JL, Realpe M, Panduro A, Roman S, Fierro NA. Rethinking the immune properties of bilirubin in viral hepatitis: from bench to bedside. Clin Transl Immunology 2015; 4:e54. [PMID: 26719800 PMCID: PMC4685441 DOI: 10.1038/cti.2015.37] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/04/2015] [Accepted: 11/15/2015] [Indexed: 02/07/2023] Open
Abstract
Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.
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Affiliation(s)
- Karla F Corral-Jara
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Jorge L Trujillo-Ochoa
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Mauricio Realpe
- Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara , Guadalajara, Mexico
| | - Arturo Panduro
- Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Sonia Roman
- Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico ; Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico
| | - Nora A Fierro
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
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Martins KAO, Cooper CL, Stronsky SM, Norris SLW, Kwilas SA, Steffens JT, Benko JG, van Tongeren SA, Bavari S. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity. EBioMedicine 2015; 3:67-78. [PMID: 26870818 PMCID: PMC4739439 DOI: 10.1016/j.ebiom.2015.11.041] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 11/23/2015] [Accepted: 11/24/2015] [Indexed: 01/08/2023] Open
Abstract
Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.
Adjuvants can prolong the protection afforded by protein-based vaccines and impact adaptive immune responses Enhanced CD4 T cell responses, helper and effector, correlate with duration of protection Durable protection from ma-EBOV is associated with Tfh frequency, Th1 antibody titers, and effector CD4 T cells Protein-based vaccines are extremely safe, but they sometimes require the addition of adjuvants to enhance immunogenicity. In this study, we compared the impact of multiple adjuvants on immunogenicity, focusing on the duration of vaccine-mediated protection in mice. We then looked at how each adjuvant impacted the immune response in order to identify correlates of that long lasting immunity. The most effective adjuvant/vaccine combinations elicited multifunctional CD4 T cell responses and a Th1-skewed antibody response. By transferring antigen-experienced CD4 T cells and serum into naïve animals, we demonstrated that both CD4 T cells and serum were critical for durable vaccine-mediated protection.
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Key Words
- Adjuvant
- BME, beta mercaptoethanol
- CD, cluster of differentiation
- DSCF, Dwass, Steel, Critchlow-Fligner
- Durable protection
- ELISA, Enzyme linked immunosorbent assay
- ELISPOT, enzyme-linked immunospot assay
- Ebola virus
- FACS, fluorescence activated cell sorting
- FBS, fetal bovine serum
- GP, glycoprotein
- IACUC, Institutional Animal Care and Use Committee
- IM, intramuscular
- IP, intraperitoneal
- IQR, interquartile range
- Immune correlates
- LN, lymph node
- MPLA, monophosphoryl lipid A
- NAb, neutralizing antibody
- Ns, not significant
- PBS, phosphate buffered saline
- PRR, pattern recognition receptor
- Pfu, plaque forming unit
- PsVNA, pseudovirion neutralization assay
- TLR, Toll-like receptor
- USAMRIID, United States Army Medical Research Institute of Infectious Diseases
- VLP, virus-like particle
- Vaccine
- ma-EBOV, mouse-adapted Ebola virus
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Affiliation(s)
- Karen A O Martins
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Christopher L Cooper
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Sabrina M Stronsky
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Sarah L W Norris
- Research Support Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Steven A Kwilas
- Virology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Jesse T Steffens
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Jacqueline G Benko
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Sean A van Tongeren
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA
| | - Sina Bavari
- Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
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50
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Hundekar S, Thorat N, Gurav Y, Lole K. Viral excretion and antibody titers in children infected with hepatitis A virus from an orphanage in western India. J Clin Virol 2015; 73:27-31. [PMID: 26521227 DOI: 10.1016/j.jcv.2015.10.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 10/09/2015] [Accepted: 10/16/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Hepatitis A is endemic in India and mainly causes sporadic infections. However, children in childcare centers, schools and orphanages are vulnerable to common-source outbreaks as they have naive hosts. OBJECTIVES To investigate hepatitis A outbreak in an orphanage from Pune, India. STUDY DESIGN Monitoring of virus excretion and anti-HAV antibody levels in hepatitis A virus (HAV) infected children. RESULTS The orphanage housed 93 children of the age 1 month-6.5 years. Analysis of the collected serum (n=78) and stool samples (n=63) revealed 20 children to be either positive for anti-HAV IgM antibodies or excreting HAV, 14 being symptomatic and 6 asymptomatic, while 32 were already anti-HAV IgG positive either due to past HAV exposure (n=7, mean log antibody titers: 2.96) or maternal antibodies (n=25, mean log antibody titers: 1.13). Serum samples, taken 4 weeks apart, did not show any significant difference in the IgM and IgG antibody levels either. However, virus excretion decreased significantly after 15 days in symptomatic children (mean log HAV RNA copies/ml 1.03+0.30), while asymptomatic children continued to excrete higher viral loads, at constant levels (mean log HAV RNA copies/ml 2.33+0.33), for up to 90 days. CONCLUSIONS Though virus excretion continued up to 90 days in all HAV infected children, asymptomatic children excreted higher viral loads for longer period and hence can contribute significantly in person-to-person virus transmission. All children should be vaccinated in such set ups.
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Affiliation(s)
| | - Neeta Thorat
- Hepatitis Division, National Institute of Virology, Pune, India
| | - Yogesh Gurav
- Hepatitis Division, National Institute of Virology, Pune, India
| | - Kavita Lole
- Hepatitis Division, National Institute of Virology, Pune, India.
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