Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans

Alexandra Schäfer; Lisa E. Gralinski; Sarah R. Leist; Brea K. Hampton; Michael A. Mooney; Kara L. Jensen; Rachel L. Graham; Sudhakar Agnihothram; Sophia Jeng; Steven Chamberlin; Timothy A. Bell; D. Trevor Scobey; Colton L. Linnertz; Laura A. VanBlargan; Larissa B. Thackray; Pablo Hock; Darla R. Miller; Ginger D. Shaw; Michael S. Diamond; Fernando Pardo Manuel de Villena; Shannon K. McWeeney; Mark T. Heise; Vineet D. Menachery; Martin T. Ferris; Ralph S. Baric

Virus Research (Jun 2024)

Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans

Alexandra Schäfer,
Lisa E. Gralinski,
Sarah R. Leist,
Brea K. Hampton,
Michael A. Mooney,
Kara L. Jensen,
Rachel L. Graham,
Sudhakar Agnihothram,
Sophia Jeng,
Steven Chamberlin,
Timothy A. Bell,
D. Trevor Scobey,
Colton L. Linnertz,
Laura A. VanBlargan,
Larissa B. Thackray,
Pablo Hock,
Darla R. Miller,
Ginger D. Shaw,
Michael S. Diamond,
Fernando Pardo Manuel de Villena,
Shannon K. McWeeney,
Mark T. Heise,
Vineet D. Menachery,
Martin T. Ferris,
Ralph S. Baric

Affiliations

Alexandra Schäfer: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding authors.
Lisa E. Gralinski: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding authors.
Sarah R. Leist: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Brea K. Hampton: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Michael A. Mooney: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
Kara L. Jensen: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Rachel L. Graham: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Sudhakar Agnihothram: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Sophia Jeng: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA
Steven Chamberlin: Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
Timothy A. Bell: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
D. Trevor Scobey: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Colton L. Linnertz: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Laura A. VanBlargan: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Larissa B. Thackray: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Pablo Hock: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Darla R. Miller: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Ginger D. Shaw: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Michael S. Diamond: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology & Immunology2, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology3, Washington University School of Medicine, St. Louis, MO, USA
Fernando Pardo Manuel de Villena: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Shannon K. McWeeney: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA
Mark T. Heise: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill NC, USA
Vineet D. Menachery: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston TX, USA; Department of Pathology and Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
Martin T. Ferris: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding authors.
Ralph S. Baric: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill NC, USA; Corresponding authors.

Journal volume & issue: Vol. 344
p. 199357

Abstract

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Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Published in Virus Research

ISSN: 1872-7492 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Microbiology; Medicine: Internal medicine: Infectious and parasitic diseases
Website: https://www.sciencedirect.com/journal/virus-research

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