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Hepatology (Baltimore, Md.)2021; 74(3); 1148-1163; doi: 10.1002/hep.31802

Pathogenesis, MicroRNA-122 Gene-Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection.

Abstract: Equine hepacivirus (EqHV) is phylogenetically the closest relative of HCV and shares genome organization, hepatotropism, transient or persistent infection outcome, and the ability to cause hepatitis. Thus, EqHV studies are important to understand equine liver disease and further as an outbred surrogate animal model for HCV pathogenesis and protective immune responses. Here, we aimed to characterize the course of EqHV infection and associated protective immune responses. Seven horses were experimentally inoculated with EqHV, monitored for 6 months, and rechallenged with the same and, subsequently, a heterologous EqHV. Clearance was the primary outcome (6 of 7) and was associated with subclinical hepatitis characterized by lymphocytic infiltrate and individual hepatocyte necrosis. Seroconversion was delayed and antibody titers waned slowly. Clearance of primary infection conferred nonsterilizing immunity, resulting in shortened duration of viremia after rechallenge. Peripheral blood mononuclear cell responses in horses were minimal, although EqHV-specific T cells were identified. Additionally, an interferon-stimulated gene signature was detected in the liver during EqHV infection, similar to acute HCV in humans. EqHV, as HCV, is stimulated by direct binding of the liver-specific microRNA (miR), miR-122. Interestingly, we found that EqHV infection sequesters enough miR-122 to functionally affect gene regulation in the liver. This RNA-based mechanism thus could have consequences for pathology. EqHV infection in horses typically has an acute resolving course, and the protective immune response lasts for at least a year and broadly attenuates subsequent infections. This could have important implications to achieve the primary goal of an HCV vaccine; to prevent chronicity while accepting acute resolving infection after virus exposure.
© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
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Publication Date: 2021-06-11 PubMed ID: 33713356PubMed Central: PMC8435542DOI: 10.1002/hep.31802Google Scholar: Lookup
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  • Journal Article
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  • Extramural
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research explores the progression of Equine hepacivirus (EqHV) infection and the associated immune responses in horses. The researchers discovered that the infection usually resolves acutely, and the immune response offers protection for at least a year against repeat infections.

Objective of the Study

  • The researchers aim was to understand the progression of EqHV infection and the corresponding protective immune responses in horses. This study becomes crucial as EqHV, being genetically the closest relative of the Hepatitis C Virus (HCV), could serve as a surrogate animal model to understand the pathogenesis and immune responses of HCV.

Method

  • Seven horses were experimentally infected with EqHV. Their health was monitored for a period of 6 months.
  • Each horse was re-exposed to the same strain of EqHV and then a different strain of the virus.

Results: Progression of EqHV Infection

  • The primary outcome of the infection was clearance; six out of seven horses cleared the infection.
  • The infection was associated with mild hepatitis evidenced by lymphocytic infiltrate and individual hepatocyte necrosis.
  • Antibody production was delayed and the pace at which the antibodies reduced was slow.

Results: Immune Responses to EqHV Infection

  • Clearance of the primary infection conferred immunity which had a non-sterilizing effect, leading to a decreased duration of viremia upon subsequent exposure.
  • However, immune responses in peripheral blood mononuclear cells were minimal, although EqHV-specific T cells were identified.
  • The researchers also found an interferon-stimulated gene signature in the liver during EqHV infection, which is similar to acute HCV in humans.

EqHV Interaction with microRNA

  • Like HCV, EqHV binds directly with the liver-specific microRNA (miR), miR-122. miR-122 helps in regulating gene expression within the liver cells.
  • During the EqHV infection, enough miR-122 is sequestered, enough to affect the gene regulation in the liver. This RNA-based mechanism might have an impact on the pathology of the disease.

Implication

  • The study indicates that horses typically experience an acute resolving course of EqHV infection and the protective immune response lasts for at least a year, giving a strong defense against subsequent infections.
  • This has important implications for the development of an HCV vaccine, aiming to prevent chronicity while accepting acute resolving infection after virus exposure.

Cite This Article

APA
Tomlinson JE, Wolfisberg R, Fahnøe U, Patel RS, Trivedi S, Kumar A, Sharma H, Nielsen L, McDonough SP, Bukh J, Tennant BC, Kapoor A, Rosenberg BR, Rice CM, Divers TJ, Van de Walle GR, Scheel TKH. (2021). Pathogenesis, MicroRNA-122 Gene-Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection. Hepatology, 74(3), 1148-1163. https://doi.org/10.1002/hep.31802

Publication

Hepatology (Baltimore, Md.)
ISSN: 1527-3350
NlmUniqueID: 8302946
Country: United States
Language: English
Volume: 74
Issue: 3
Pages: 1148-1163

Researcher Affiliations

Tomlinson, Joy E
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY.
Wolfisberg, Raphael
  • Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Fahnøe, Ulrik
  • Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Patel, Roosheel S
  • Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY.
Trivedi, Sheetal
  • Center for Vaccines and Immunity, Research Institute at Nationwide Children's Hospital, Columbus, OH.
Kumar, Arvind
  • Center for Vaccines and Immunity, Research Institute at Nationwide Children's Hospital, Columbus, OH.
Sharma, Himanshu
  • Center for Vaccines and Immunity, Research Institute at Nationwide Children's Hospital, Columbus, OH.
Nielsen, Louise
  • Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
McDonough, Sean P
  • Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY.
Bukh, Jens
  • Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Tennant, Bud C
  • Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY.
Kapoor, Amit
  • Center for Vaccines and Immunity, Research Institute at Nationwide Children's Hospital, Columbus, OH.
Rosenberg, Brad R
  • Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY.
Rice, Charles M
  • Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY.
Divers, Thomas J
  • Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY.
Van de Walle, Gerlinde R
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY.
Scheel, Troels K H
  • Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
  • Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY.

MeSH Terms

  • Animals
  • Disease Progression
  • Gene Expression Regulation
  • Hepacivirus / immunology
  • Hepacivirus / metabolism
  • Hepatitis, Viral, Animal / genetics
  • Hepatitis, Viral, Animal / immunology
  • Horses
  • Liver / immunology
  • Liver / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • MicroRNAs / metabolism
  • T-Lymphocytes / immunology
  • Transcriptome

Grant Funding

  • K08 AI141767 / NIAID NIH HHS
  • R01 AI137567 / NIAID NIH HHS
  • R01 AI151175 / NIAID NIH HHS
  • S10 OD026880 / NIH HHS

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