T cells protect against hepatitis A virus infection and limit infection-induced liver injury

Ichiro Misumi; Joseph E Mitchell; Makayla M Lund; John M Cullen; Stanley M Lemon; Jason K Whitmire

doi:10.1016/j.jhep.2021.07.019

T cells protect against hepatitis A virus infection and limit infection-induced liver injury

J Hepatol. 2021 Dec;75(6):1323-1334. doi: 10.1016/j.jhep.2021.07.019. Epub 2021 Jul 29.

Authors

Ichiro Misumi¹, Joseph E Mitchell², Makayla M Lund³, John M Cullen⁴, Stanley M Lemon⁵, Jason K Whitmire⁶

Affiliations

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.

Keywords: Hepatitis A Virus; T cell vaccine; T cells; liver infection; liver pathogenesis; mice; type-1 interferons.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
Disease Models, Animal
Hepatitis A / drug therapy
Hepatitis A / epidemiology
Hepatitis A / prevention & control*
Hepatitis A virus / drug effects
Hepatitis A virus / pathogenicity
Liver Diseases / drug therapy
Liver Diseases / epidemiology
Liver Diseases / prevention & control*
Mice
North Carolina
Statistics, Nonparametric
T-Lymphocytes / metabolism*
T-Lymphocytes / physiology

Abstract

Publication types

MeSH terms

Grants and funding