Genetic loci regulate Sarbecovirus pathogenesis : A comparison across mice and humans
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:344 |
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| Enthalten in: |
Virus research - 344(2024) vom: 18. Apr., Seite 199357 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schäfer, Alexandra [VerfasserIn] |
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| Links: |
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| Themen: |
Comparative Study |
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| Anmerkungen: |
Date Completed 24.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.virusres.2024.199357 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Genetic loci regulate Sarbecovirus pathogenesis |b A comparison across mice and humans |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Host susceptibility loci | |
| 650 | 4 | |a Pathogenesis | |
| 650 | 4 | |a SARS-CoV | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a Zoonotic CoV | |
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| 700 | 1 | |a Gralinski, Lisa E |e verfasserin |4 aut | |
| 700 | 1 | |a Leist, Sarah R |e verfasserin |4 aut | |
| 700 | 1 | |a Hampton, Brea K |e verfasserin |4 aut | |
| 700 | 1 | |a Mooney, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Jensen, Kara L |e verfasserin |4 aut | |
| 700 | 1 | |a Graham, Rachel L |e verfasserin |4 aut | |
| 700 | 1 | |a Agnihothram, Sudhakar |e verfasserin |4 aut | |
| 700 | 1 | |a Jeng, Sophia |e verfasserin |4 aut | |
| 700 | 1 | |a Chamberlin, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Bell, Timothy A |e verfasserin |4 aut | |
| 700 | 1 | |a Scobey, D Trevor |e verfasserin |4 aut | |
| 700 | 1 | |a Linnertz, Colton L |e verfasserin |4 aut | |
| 700 | 1 | |a VanBlargan, Laura A |e verfasserin |4 aut | |
| 700 | 1 | |a Thackray, Larissa B |e verfasserin |4 aut | |
| 700 | 1 | |a Hock, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Darla R |e verfasserin |4 aut | |
| 700 | 1 | |a Shaw, Ginger D |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a de Villena, Fernando Pardo Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a McWeeney, Shannon K |e verfasserin |4 aut | |
| 700 | 1 | |a Heise, Mark T |e verfasserin |4 aut | |
| 700 | 1 | |a Menachery, Vineet D |e verfasserin |4 aut | |
| 700 | 1 | |a Ferris, Martin T |e verfasserin |4 aut | |
| 700 | 1 | |a Baric, Ralph S |e verfasserin |4 aut | |
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