Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice
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Background & Aims: 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. Approach & Results: 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Hepatology |
| Vol/bind | 79 |
| Udgave nummer | 1 |
| Sider (fra-til) | 183-197 |
| ISSN | 0270-9139 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
The authors thank the technical support from the UNC High Throughput Sequencing Facility. This facility is supported by the University Cancer Research Fund, Comprehensive Cancer Center Core Support grant (P30-CA016086), and UNC Center for Mental Health and Susceptibility grant (P30-ES010126). They also thank Louise B. Christensen (Department of Clinical Microbiology, University of Copenhagen) for laboratory assistance and the Department of Clinical Microbiology, Hvidovre Hospital, for access to Illumina miSeq equipment. Collaborative Cross (CC) mice were obtained from 2017 to 2021 from the Systems Genetics Core Facility at the University of North Carolina at Chapel Hill. They also thank Dr. Amit Kapoor from the University of Ohio and Dr. Brad Rosenberg from Mt. Sinai Medical School for a helpful and insightful discussion of this work.
Funding Information:
This work was funded by R01 grant from the National Institute of Allergy and Infectious Disease (NIAID, AI131688 to Charles M. Rice), a U19 grant from NIAID (U19AI100625 to Ralph Baric and Mark Heise), the Independent Research Fund Denmark (1030-00426 to Troels K.H. Scheel), Advanced Grant 4004-00598 to Jens Bukh), the Danish Cancer Society (R204-A12639 to Jens Bukh and Troels K.H. Scheel), the Novo Nordisk Foundation (Distinguished Investigator Grant NNF19OC0054518 and Tandem NNF19OC0055462 to Jens Bukh), and the European Research Council (Starting Grant 802899 to Troels K. H. Scheel). Raphael Wolfisberg was supported by an Early Postdoc Mobility Fellowship (P2BEP3_178527) and a Postdoc Mobility Fellowship (P400PB-183952) from the Swiss National Science Foundation.
Funding Information:
Timothy P. Sheahan received grants from GlaxoSmithKline, Regeneron, and ViiV Healthcare. The remaining authors have no conflicts to report.
Publisher Copyright:
© 2024 John Wiley and Sons Inc.. All rights reserved.
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