Ichiro Misumi1, Joseph E Mitchell2, Makayla M Lund3, John M Cullen4, Stanley M Lemon5, Jason K Whitmire6. 1. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: imisumi@email.unc.edu. 2. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. 3. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. 4. Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27607, USA. 5. Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. 6. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jwhitmir@email.unc.edu.
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.
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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