A Multitrait Locus Regulates Sarbecovirus Pathogenesis
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Schäfer, A, et al. A Multitrait Locus Regulates Sarbecovirus Pathogenesis. American Society for Microbiology, 2022. https://doi.org/10.17615/q0t7-5r51APA
Schäfer, A., Leist, S., Gralinski, L., Martinez, D., Winkler, E., Okuda, K., Hawkins, P., Gully, K., Graham, R., Scobey, D., Bell, T., Hock, P., Shaw, G., Loome, J., Madden, E., Anderson, E., Baxter, V., Taft Benz, S., Zweigart, M., May, S., Dong, S., Clark, M., Miller, D., Lynch, R., Heise, M., Tisch, R., Boucher, R., De Villena, F., Montgomery, S., Diamond, M., Ferris, M., & Baric, R. (2022). A Multitrait Locus Regulates Sarbecovirus Pathogenesis. American Society for Microbiology. https://doi.org/10.17615/q0t7-5r51Chicago
Schäfer, A, S.R Leist, L.E Gralinski, D.R Martinez, E.S Winkler, K Okuda, P.E Hawkins et al. 2022. A Multitrait Locus Regulates Sarbecovirus Pathogenesis. American Society for Microbiology. https://doi.org/10.17615/q0t7-5r51- Creator
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Schäfer, A
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Leist, S.R
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Gralinski, L.E
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Martinez, D.R
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Winkler, E.S
- Other Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
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Okuda, K
- Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
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Hawkins, P.E
- Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
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Gully, K.L
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Graham, R.L
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Scobey, D.T
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Bell, T.A
- Affiliation: School of Medicine, Department of Genetics
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Hock, P
- Affiliation: School of Medicine, Department of Genetics
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Shaw, G.D
- Affiliation: School of Medicine, Department of Genetics
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Loome, J.F
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Madden, E.A
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Anderson, E
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Baxter, V.K
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Taft-Benz, S.A
- Affiliation: School of Medicine, Department of Genetics
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Zweigart, M.R
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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May, S.R
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Dong, S
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Clark, M
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Miller, D.R
- Affiliation: School of Medicine, Department of Genetics
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Lynch, R.M
- Affiliation: School of Medicine, Department of Genetics
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Heise, M.T
- Affiliation: School of Medicine, Department of Genetics
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Tisch, R
- Affiliation: School of Medicine, Department of Microbiology and Immunology
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Boucher, R.C
- Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
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de Villena, F.P.M
- Affiliation: School of Medicine, Department of Genetics
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Montgomery, S.A
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Diamond, M.S
- Other Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
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Ferris, M.T
- Affiliation: School of Medicine, Department of Genetics
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Baric, R.S
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
- 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 Genomewide 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.
- Date of publication
- 2022
- Keyword
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- mBio
- Journal volume
- 13
- Journal issue
- 4
- Language
- English
- Version
- Publisher
- Funder
- National Institutes of Health, NIH: 38 75N93020F00001, HHSN272201700036I
- Howard Hughes Medical Institute, HHMI
- National Institute of Allergy and Infectious Diseases, NIAID: AI100625, AI149644
- Burroughs Wellcome Fund, BWF
- ISSN
- 2161-2129
- Publisher
- American Society for Microbiology
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