# Murine Model of Human Hepatitis A

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $388,750

## Abstract

PROJECT ABSTRACT
Although hepatotropic viruses are important causes of human disease, the intrahepatic immune response to
hepatitis viruses is poorly understood due to a lack of tractable small animal models. In this Multi-PI
application, an experienced virologist teams with an accomplished viral immunologist to propose experiments
aimed at better understanding the intrahepatic immune response to a human hepatitis virus using a novel
murine model in which hepatitis A virus (HAV) infection of mice lacking the type I interferon (IFN) receptor
(Ifnar1-/-) recapitulates critical features of type A hepatitis in humans. Preliminary data from this model
demonstrate (1) that the capacity of HAV to evade MAVS-mediated type I interferon (IFNα/β) responses
defines its host species range, and (2) that acute HAV-induced liver injury stems from IFN-independent intrinsic
hepatocellular apoptosis with secondary inflammation that unexpectedly results from MAVS and IRF3/7
signaling. This new murine model thus reveals a previously undefined link between innate immune responses
to virus infection and acute liver injury, providing a novel paradigm for viral pathogenesis in the liver that is
likely relevant to other hepatitis viruses. The HAV 3ABC protease cleaves human MAVS, disrupting IFN
responses in human cells, but cannot cleave the murine MAVS ortholog due to sequence differences. We
hypothesize that this inability of HAV to disrupt murine MAVS-mediated IFN responses renders mice
nonpermissive for infection, and will test this hypothesis in Aim 1 using mice with CRISPR/Cas9 editing of the
Mavs gene that renders the expressed protein susceptible to 3ABC cleavage. Aim 1 will also define cell types
that sense HAV and in which IFN-induced gene expression controls HAV replication in the liver, and ascertain
the role played by type III IFNλ in countering infection in the liver and intestinal mucosa. Aim 2 will define
differences in protective, antiviral IFN-induced transcriptional responses versus pro-pathogenic IRF3-induced
gene expression, examine the role of IFIT proteins in the pro-pathogenic response, and determine whether
transcription-independent functions of activated IRF3 control infection or drive acute liver injury. Aim 3 will
examine the adaptive cellular immune response to HAV infection and how it is linked to the early innate
immune response. Aim 3 will address the role of HAV-specific T cells in virus control and define innate
mechanisms regulating these responses in the liver. The proposed studies will further refine a unique and
valuable animal model and provide novel insight into the interplay between innate and adaptive immunity and
acute liver injury in the context of hepatotropic virus infection.

## Key facts

- **NIH application ID:** 10102175
- **Project number:** 5R01AI131685-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Stanley M. Lemon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2017-03-06 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102175

## Citation

> US National Institutes of Health, RePORTER application 10102175, Murine Model of Human Hepatitis A (5R01AI131685-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102175. Licensed CC0.

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