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 VillenaShannon K. McWeeney, Mark T. Heise, Vineet D. Menachery, Martin T. Ferris, Ralph S. Baric

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Article number199357
JournalVirus Research
StatePublished - Jun 2024


  • Host susceptibility loci
  • Pathogenesis
  • SARS-CoV
  • SARS-CoV-2
  • Zoonotic CoV

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases
  • Cancer Research


Dive into the research topics of 'Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans'. Together they form a unique fingerprint.

Cite this