Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

Abstract

Background & Aims: Human genetic variation is thought to guide the outcome of hepatitis C virus (HCV) infection but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus (NrHV), closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in two weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. Approach & Results: We infected a panel of CC strains with NrHV and identified several that failed to clear virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation and the capacity to develop liver fibrosis varied among infected CC strains. Conclusions: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of virus and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

“…CC strains have been a useful tool to relate genotype to phenotype in mice for many disease states, infectious and otherwise. For pathogenic human RNA viruses, CC strains have enabled understanding of host genetics impacting a variety of viruses, including SARS-CoV 31,32,33,34,35,36 , influenza virus 37,38,39,40,41,42 , Ebola virus 43,44 , West Nile virus 45,46,47,48 , Theiler's murine encephalitis virus 49,50,51,52,53 , lymphocytic choriomeningitis virus 54 , Zika virus 55 , SARS-CoV-2 17,36 , Rift Valley fever virus 56 , Powassan virus 57 , and recently, Norway rat hepacivirus 58 , which is closely related to HCV. These studies have revealed mouse genetic background impacts overall susceptibility to infection, viral burdens, host survival, levels of tissue inflammation, innate and adaptive immune responses, and differential gene expression after virus infection.…”