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.

Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo

“…Lethality after infection with West Nile virus [15] or Powassan virus [16] were also described, although there is likely contribution from the defective Oas1b allele that CC071 has inherited from 129S1/SvImJ. CC071 was also one of the most susceptible CC strains to Rift Valley Fever virus infection [17] and to hepacivirus with long-term viral persistence [21]. Because of its unique genetic background, this strain will be increasingly useful for infectious diseases studies, which underlines the importance of deciphering the mechanisms of its susceptibility to each pathogen.…”

“…The Irf3 KO allele results in a band at 877pb while the Irf3 71 allele results in no band. Individuals 1,5,11,14,15,16,17,19,21,22 and…”