Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Abstract

Sarbecovirus (CoV) infections, including Severe Acute Respiratory CoV (SARS-CoV) and SARS-CoV-2, are considerable human threats. Human GWAS studies have recently identified loci associated with variation in SARS-CoV-2 susceptibility. However, genetically tractable models that reproduce human CoV disease outcomes are needed to mechanistically evaluate genetic determinants of CoV susceptibility. We used the Collaborative Cross (CC) and human GWAS datasets to elucidate host susceptibility loci that regulate CoV infections and to identify host quantitative trait loci that modulate severe CoV and pan-CoV disease outcomes including a major disease regulating loci including CCR9. CCR9 ablation resulted in enhanced titer, weight loss, respiratory dysfunction, mortality, and inflammation, providing mechanistic support in mitigating protection from severe SARS-CoV-2 pathogenesis across species. This study represents a comprehensive analysis of susceptibility loci for an entire genus of human pathogens conducted, identifies a large collection of susceptibility loci and candidate genes that regulate multiple aspects type-specific and cross-CoV pathogenesis, and also validates the paradigm of using the CC platform to identify common cross-species susceptibility loci and genes for newly emerging and pre-epidemic viruses.

Using the Collaborative Cross and Diversity Outbred Mice in Immunology

“…The CC and DO mouse models have shown exceptional promise in identifying loci that contribute to our understanding of the genetic regulation of the differential outcomes to various infectious diseases caused by viral (influenza, SARS‐CoV1, SARS‐CoV2, Ebola, Zika, West Nile, TMEV, etc. ), bacterial (Pseudomonas, Klebsiella pneumoniae, Salmonella enterica Typhimurium ), mycobacterial (TB), fungal ( Aspergillus fumigatus, Blastomyces dermatitidis ), prion, protist ( Plasmodium chabaudi ), or helminth parasitic pathogens ( S. venezuelensis ) (Durrant et al., 2011; Graham et al., 2021; Green et al., 2016; Kamiya, Davis, Greischar, Schneider, & Mideo, 2021; Kohn et al., 2022; Lorè et al., 2020; Manet et al., 2020; Matsushita et al., 2021; Noll et al., 2020; Perez Gomez et al., 2021; Price et al., 2020; Schäfer et al., 2021; Smith et al., 2022; Vered, Durrant, Mott, & Iraqi, 2014; Xiong et al., 2014; Zhang et al., 2018).…”