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

Authors :
Ariane J. Brown
John J. Won
Raphael Wolfisberg
Ulrik Fahnøe
Nicholas Catanzaro
Ande West
Fernando R. Moreira
Mariana Nogueira Batista
Martin T. Ferris
Colton L. Linnertz
Sarah R. Leist
Cameron Nguyen
Gabriela De la Cruz
Bentley R. Midkiff
Yongjuan Xia
Stephanie A. Montgomery
Eva Billerbeck
Jens Bukh
Troels K.H. Scheel
Charles M. Rice
Timothy P. Sheahan
Publication Year :
2023
Publisher :
Cold Spring Harbor Laboratory, 2023.

Abstract

Background & AimsHuman 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 & ResultsWe 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.ConclusionsThese 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........24302a1c3ae6256ada68575f8a75f1a9
Full Text :
https://doi.org/10.1101/2023.03.18.533278