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

• First , we introduce and describe the feasibility of the CC as a screening platform for complex genetic regulation of SARS-Like group 2B coronaviruses pathogenesis. • Second , we define and describe 2 different CC-derived screening populations (broad F1 screening, and targeted intercrosses) resulting in identification of many significant host susceptibility loci. • Third , we show how candidate genes can be identified under susceptibility loci and validated for roles in CoV pathogenesis, such as Trim14. • Lastly , we report that ∼70 % of our identified QTL in mice contain one human GWAS hit, that have been shown to be associated with the development do severe COVID-19, showing potential cross-species mechanisms underlying sarbecovirus pathogenesis. 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. [ABSTRACT FROM AUTHOR]