Biomaterial Database

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice. 2024

Ariane J Brown, and John J Won, and Raphael Wolfisberg, and Ulrik Fahnøe, and Nicholas Catanzaro, and Ande West, and Fernando R Moreira, and Mariana Nogueira Batista, and Martin T Ferris, and Colton L Linnertz, and Sarah R Leist, and Cameron Nguyen, and Gabriela De la Cruz, and Bentley R Midkiff, and Yongjuan Xia, and Mia D Evangelista, and Stephanie A Montgomery, and Eva Billerbeck, and Jens Bukh, and Troels K H Scheel, and Charles M Rice, and Timothy P Sheahan

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, 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 2 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. We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the 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 viruses 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.