Defining Immune Dysfunction in Chronic Hepacivirus Infection at Single Cell Resolution

PROJECT SUMMARY/ABSTRACT
Hepatitis C virus (HCV) is a hepacivirus that chronically infects an estimated 58 million people worldwide and
can result in end-stage liver disease. It has been well established that ineffectual T cell responses contribute to
the establishment and maintenance of chronic HCV infection. Namely, T cell exhaustion, wherein T cells lose
effector and proliferative functions due to chronic antigen stimulation, is a common phenomenon observed in
chronic HCV patients and is known to enable viral persistence. However, it has proven difficult to define
mechanistically different aspects of immune dysfunction in chronic hepacivirus infection, in part due to a lack of
animal models that can support chronic HCV infection and elicit a similar immune response. Norway rat
hepacivirus (NrHV) is a close relative of HCV that can establish chronic infection in immunocompetent mice and
recapitulate key features of chronic HCV, thus serving as a physiologically relevant and experimentally tractable
model for studying the immune response to chronic hepacivirus infection. Despite its promise as a model for
studying various aspects of the immune response to chronic hepacivirus infection, an in-depth characterization
of the immune landscape over time in chronic NrHV infection in mice has yet to be performed.
Here, I propose performing high-resolution immunological characterizations of this novel murine model of chronic
hepacivirus infection to study the evolution of immune dysfunction over the course of infection and to better
understand the molecular drivers of T cell exhaustion and viral persistence in chronic hepacivirus infection. First,
I will model transcriptional regulatory networks in chronic hepacivirus infection and other contexts of T cell
exhaustion to identify common and distinct transcriptional programs defining immune dysfunction (Aim 1). My
preliminary findings from existing transcriptomic data on this model suggest that there are two distinct lineages
of exhausted T cells in NrHV infection which may recognize viral antigen. Therefore, I will define the phenotypic
features of the two exhausted lineages in this model to elucidate the relationship between TCR specificity and
cellular phenotypes of virus-specific exhausted T cells (Aim 2). These studies are expected to ultimately
contribute to our understanding of the immunological mechanisms that drive T cell exhaustion, hinder hepacivirus
clearance, and contribute to the pathogenesis of viral liver disease in chronic HCV infection. The proposed
project provides an excellent training opportunity and environment that encompasses mastering cutting-edge
single cell and immunological techniques, professional development, and mentorship that support my goals and
growth as an independent research scientist.

Grant Number: 5F31AI186462-02
NIH Institute/Center: NIH
Principal Investigator: Tesia Bobrowski