A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Alexandra Schäfer; Sarah R. Leist; Lisa E. Gralinski; David R. Martinez; Emma S. Winkler; Kenichi Okuda; Padraig E. Hawkins; Kendra L. Gully; Rachel L. Graham; D. Trevor Scobey; Timothy A. Bell; Pablo Hock; Ginger D. Shaw; Jennifer F. Loome; Emily A. Madden; Elizabeth Anderson; Victoria K. Baxter; Sharon A. Taft-Benz; Mark R. Zweigart; Samantha R. May; Stephanie Dong; Matthew Clark; Darla R. Miller; Rachel M. Lynch; Mark T. Heise; Roland Tisch; Richard C. Boucher; Fernando Pardo Manuel de Villena; Stephanie A. Montgomery; Michael S. Diamond; Martin T. Ferris; Ralph S. Baric

doi:10.1128/mbio.01454-22

mBio (Aug 2022)

A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Alexandra Schäfer,
Sarah R. Leist,
Lisa E. Gralinski,
David R. Martinez,
Emma S. Winkler,
Kenichi Okuda,
Padraig E. Hawkins,
Kendra L. Gully,
Rachel L. Graham,
D. Trevor Scobey,
Timothy A. Bell,
Pablo Hock,
Ginger D. Shaw,
Jennifer F. Loome,
Emily A. Madden,
Elizabeth Anderson,
Victoria K. Baxter,
Sharon A. Taft-Benz,
Mark R. Zweigart,
Samantha R. May,
Stephanie Dong,
Matthew Clark,
Darla R. Miller,
Rachel M. Lynch,
Mark T. Heise,
Roland Tisch,
Richard C. Boucher,
Fernando Pardo Manuel de Villena,
Stephanie A. Montgomery,
Michael S. Diamond,
Martin T. Ferris,
Ralph S. Baric

Affiliations

Alexandra Schäfer: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Sarah R. Leist: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Lisa E. Gralinski: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
David R. Martinez: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Emma S. Winkler: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
Kenichi Okuda: Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Padraig E. Hawkins: Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Kendra L. Gully: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Rachel L. Graham: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
D. Trevor Scobey: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Timothy A. Bell: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Pablo Hock: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Ginger D. Shaw: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Jennifer F. Loome: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Emily A. Madden: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Elizabeth Anderson: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Victoria K. Baxter: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Sharon A. Taft-Benz: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Mark R. Zweigart: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Samantha R. May: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Stephanie Dong: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Matthew Clark: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Darla R. Miller: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Rachel M. Lynch: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Mark T. Heise: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Roland Tisch: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Richard C. Boucher: Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Fernando Pardo Manuel de Villena: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Stephanie A. Montgomery: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Michael S. Diamond: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
Martin T. Ferris: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Ralph S. Baric: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

DOI: https://doi.org/10.1128/mbio.01454-22
Journal volume & issue: Vol. 13, no. 4

Abstract

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ABSTRACT Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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