TY - JOUR
T1 - Genetic loci regulate Sarbecovirus pathogenesis
T2 - A comparison across mice and humans
AU - Schäfer, Alexandra
AU - Gralinski, Lisa E.
AU - Leist, Sarah R.
AU - Hampton, Brea K.
AU - Mooney, Michael A.
AU - Jensen, Kara L.
AU - Graham, Rachel L.
AU - Agnihothram, Sudhakar
AU - Jeng, Sophia
AU - Chamberlin, Steven
AU - Bell, Timothy A.
AU - Scobey, D. Trevor
AU - Linnertz, Colton L.
AU - VanBlargan, Laura A.
AU - Thackray, Larissa B.
AU - Hock, Pablo
AU - Miller, Darla R.
AU - Shaw, Ginger D.
AU - Diamond, Michael S.
AU - de Villena, Fernando Pardo Manuel
AU - McWeeney, Shannon K.
AU - Heise, Mark T.
AU - Menachery, Vineet D.
AU - Ferris, Martin T.
AU - Baric, Ralph S.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
KW - Host susceptibility loci
KW - Pathogenesis
KW - SARS-CoV
KW - SARS-CoV-2
KW - Zoonotic CoV
UR - http://www.scopus.com/inward/record.url?scp=85188705382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85188705382&partnerID=8YFLogxK
U2 - 10.1016/j.virusres.2024.199357
DO - 10.1016/j.virusres.2024.199357
M3 - Article
C2 - 38508400
AN - SCOPUS:85188705382
SN - 0168-1702
VL - 344
SP - 199357
JO - Virus Research
JF - Virus Research
M1 - 199357
ER -