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

doi:10.1016/j.virusres.2024.199357

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

Virus Res. 2024 Jun:344:199357. doi: 10.1016/j.virusres.2024.199357. Epub 2024 Mar 23.

Authors

Alexandra Schäfer¹, Lisa E Gralinski², Sarah R Leist³, Brea K Hampton⁴, Michael A Mooney⁵, Kara L Jensen³, Rachel L Graham³, Sudhakar Agnihothram³, Sophia Jeng⁶, Steven Chamberlin⁷, Timothy A Bell⁸, D Trevor Scobey³, Colton L Linnertz⁸, Laura A VanBlargan⁹, Larissa B Thackray⁹, Pablo Hock⁸, Darla R Miller¹⁰, Ginger D Shaw¹⁰, Michael S Diamond¹¹, Fernando Pardo Manuel de Villena¹⁰, Shannon K McWeeney¹², Mark T Heise¹³, Vineet D Menachery¹⁴, Martin T Ferris¹⁵, Ralph S Baric¹⁶

Affiliations

¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].
³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ 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.
⁵ 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.
⁶ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA.
⁷ 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.
⁸ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].
¹⁶ 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. Electronic address: [email protected].

Abstract

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.

Keywords: Host susceptibility loci; Pathogenesis; SARS-CoV; SARS-CoV-2; Zoonotic CoV.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Comparative Study

MeSH terms

Animals
COVID-19 / virology
Coronavirus Infections / genetics
Coronavirus Infections / virology
Disease Models, Animal
Genome-Wide Association Study
Humans
Mice
Quantitative Trait Loci*
SARS-CoV-2 / genetics
Tripartite Motif Proteins / genetics
Virus Replication

Substances

Tripartite Motif Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding