Sarbecovirus disease susceptibility is conserved across viral and host models

Abstract

Coronaviruses have caused three severe epidemics since the start of the 21^st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

Keywords: COVID-19; Collaborative Cross; Coronavirus; Genetics; Mouse models; QTL; SARS; SARS-CoV; SARS-CoV-2.

Graphical abstract

Fig. 1

CC strains demonstrate variable response to SARS-CoV MA15 infection. A) Weight loss as shown by strain means for four dpi, B) lung congestion score, and C) log-transformed viral titer following infection with SARS-CoV MA15 in four female mice from each of 10 CC strains. D) Weight loss, E) lung congestion scores and F) log-transformed viral titer in four female mice from each of three CC strains, chosen for their divergent responses in the initial screen. Strain means and standard deviations for congestion score and viral titer are indicated by horizontal bars. P-values for all pairwise comparisons as determined by Tukey's HSD test are in Supplemental Table 1.

Fig. 2

Disease phenotypes after SARS-CoV MA15, SARS-CoV-2 MA10, and HKU3-CoV MA in CC006xCC044 F2 mice. (A) Weight loss in n = 391 F2 mice after infection with SARS-CoV MA15. (B) Weight loss in n = 274 F2 mice after infection with SARS-CoV-2 MA10. (C) Weight loss in n = 90 F2 mice after infection with HKU3-CoV MA. Red and blue lines in A-C represent average body weight trajectory of CC006 and CC044 mice, respectively, after infection with SARS-CoV MA15 (see Fig. 1A). (D) Distribution of congestion scores in F2 mice, colored by infection group.

Fig. 3

Genetic architecture of disease severity following SARS-CoV MA15 and SARS-CoV-2 MA10 infection in F2 mice. Genome scans from QTL mapping on A) weight loss on day 3 and B) congestion score in SARS-CoV MA15-infected F2 mice, and C) weight loss on day 3 and D) congestion score in SARS-CoV-2 MA10-infected F2 mice. Solid and dashed lines represent 5% and 10% significance thresholds, respectively. HrS43 overlaps with HrS26 previously mapped for SARS-CoV MA15 in CC011xCC074 F2 cross.

Fig. 4

HrS43 genotype effect in SARS-CoV MA15-, SARS-CoV-2 MA10- and HKU3-CoV MA-infected mice. Relationship between genotype at HrS43 peak marker S3N094839317 and weight loss (AAC) in A) SARS-CoV MA15-infected mice (genome-wide adjusted P = 5.7 × 10⁻⁴), B) SARS-CoV-2 MA10-infected mice (genome-wide adjusted P = 9.7 × 10⁻³), and C) HKU3-CoV MA-infected mice (P = 0.02).