Coronaviruses have caused three severe epidemics since the start of the 21st 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 mo use genetic reference panel and idenetifd 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 g enetic 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).

loci (QTL) mapping in SARS-CoV- and SARS-CoV-2-infected F2 mice idenetifd genetic loci associated with disease severity. Specicfially, we idenetifd seven loci associated with variation in outcome following infection with either virus, including one,

both groups. Three of these QTL, including HrS45, were also associated with HKU3-CoV MA outcome. HrS45 overlaps with a QTL previously reported by our lab that is associated with SARSCoV 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 rfist 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.

Over the last three decades, three zoonotic coronaviruses have emerged in humans: SARS-CoV in 2003 (Zhong et al., 2003), MERS-CoV in 2012 (Hijawi et al., 2013) and SARS-CoV-2 in late 2019 (Zhou et al., 2020a, Zhou et al., 2020b). SARS-CoV-2 is the causative agent of the ongoing COVID19 pandemic. Despite the public health emergency being declared over as of May 11th, 2023 (hpts://www.cdc.gov/coronavirus/2019 -ncov/your-health/end-of-phe.html), acute infections with constantly evolving Variants of Concern (VoCs) as well as post-acute sequelae weeks to months aeftr infection

pose ongoing global health burdens. Furthermore, it has been shown that coronaviruses in natural animal reservoirs like bats are poised for human emergence (Menachery et al., 2015) and that climate change increases the likelihood of future transmission of viruses from animal to humans (Carlson et al., 2022). Despite a surge in worldwide eofrts in understanding disease mechanisms for countermeasure development, many aspects of the disease caused by SARS-CoV-2 specicfially , but also sarbecoviruses and other coronaviruses in general, remain elusive. Thus, the need to understand mechanisms driving disease progression, outcome, and ways to intervene remains of high priority.

Murine model systems are one of the most widely used biomedical research tools with which to investigate infectious disease mechanisms and pathogenesis in vivo. Mouse-adapted versions of both viruses (SARS-CoV MA15 (Roberts et al., 2007) and SARS-CoV-2 MA10 (Leist et al., 2020) have been used in multiple studies showing their potential to replicate acute respiratory distress syndrome (ARDS) as seen in the human population (Yan et al., 2022, Thieulent et al., 2023, Leist et al., 2020). Even with these available tools, most of these studies focus on one or a few classical mouse strains (e.g. BALB/c or C57BL/6 (Gralinski et al., 2013, Adams et al., 2023)), which neglects the eefct of host genetic background on driving disease outcomes. Genetically diverse mouse genetic reference panels allow us to examine host genetic factors contributing to viral disease severity and outcomes.

Host susceptibility loci that regulate coronavirus infection response were rfist reported with mouse hepatis virus (

MHV) in mice (Ohtsuka and Taguchi, 1997). Over the past decade, we have utilized the Collaborative Cross (CC) genetic reference panel to study a variety of viral pathogens, including the idenctifation of several genetic loci associated with SARS-CoV infectious outcomes (Ferris et al., 2013, Noll et al., 2020, Gralinski et al., 2015, Maurizio et al., 2018, Schafer et al., 2022). The CC is a large panel of recombinant inbred (RI) strains derived from eight genetically diverse founder strains and designed specicfially for complex trait analysis and systems genetics approaches (i nitially desc ribed in (Threadgill et al., 2011) and reviewed more fully in (Leist and Baric, 2018)). Herein, we use an F2 cross between coronavirus-susceptible mice to more thoroughly investigate the genetic architecture underlying both SARS -CoV and SARS-CoV-2 disease outcomes, as well as assess concordance with a pre-emergent (HKU3-CoV) virus.

We purchased a set of 10 CC strains (listed in Fig 1.A-C) from the System’s Genetics Core Facility (SGCF) at UNC, and screened them for divergent responses to SARS-CoV MA15 infection . Four 10-week-old female mice from each of these ten CC strains were intra-nasally infected with 104 plaque-forming units (PFU) of mouse-adapted SARS-CoV MA15 (Roberts et al., 2007), and changes in body weight were monitored for four days post-infection (dpi) . Lung congestion scores as a gross evaluation of histopathological changes at the time point of harvest as well as viral titer in lungs on day 4 were measured. Viral titers were determined by plaque assay , as previously described (Schafer et al., 2022). We observed highly variant disease outcomes in terms of weight loss (Fig. 1A), congestion scores (Fig. 1B) and viral titer ( Fig. 1C) across these ten strains. From this screen we idenetifd

CC006 as susceptible and CC044 as resistant to severe disease. CC006 exhibited a severe disease response marked by 50% mortality and 19% loss of body weight on average in surviving mice by day 4 post-infection. In contrast, CC044 mice were resistant to disease, with no mortality and lilte if any change in body weight on average. The overall weight loss trajectories (area above the curve, AAC) of CC006 and CC044 mice were signicfiantly diefrent from each other (p = 6x10-3, Tukey’s HSD). CC006 mice also exhibited signicfiantly higher congestion scores than CC044 mice (p = 1x10-4, Tukey’s HSD test). Importantly, while these strains had divergent disease responses, they showed similar viral loads (p = 0.99, Tukey’s HSD test), suggesting that variation in disease severity is due to variable host response rather than variation in viral burden. Following the initial screen, we repeated this experiment with CC006, CC044, and CC023/GeniUnc and validated their divergent responses (Fig. 1D-F). Weight loss trajectories (Fig. 1D, p = 3x10-4) but not congestion scores ( Fig. 1E, p = 0.13) were signicfiantly diefrent from each other between CC006 and CC044 in this repeat experiment. As in the original screen, ttier was not signicfiantly diefrent between CC006 and CC044 mice ( Fig. 1F, p = 0.53). As such, CC006 and CC044 seemed strong candidates to generate a targeted F2 cross for genetic mapping. 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.

We generated a genetic mapping population of CC006xCC044 F2 mice, using a balanced breeding design as we have previously described (Schafer et al., 2022, Gralinski et al., 2017). In total, we generated 755 F2 mice from all four grandparental combinations . These F2 mice were exposed to one of three coronaviruses: the clade Ia sarbecovirus SARS-CoV MA15 (n=391), the clade Ib sarbecovirus SARS-CoV-2 MA10 (n=274) and also the clade II sarbecovirus HKU3-CoV (HKU3-CoV MA) (n=90), a mouse-adapted bat virus (Becker et al., 2008). We assessed disease severity and progression by measuring weight loss for four days following infection, and at 4 dpi, we euthanized the mice and assessed their overall lung pathology in the form of a congestion score. Weight loss following SARS-CoV MA15 (Fig. 2A) and SARS-CoV-2 MA10 (Fig. 2B) infection in these F2 mice expanded the range of what was observed in the parental strains following SARSCoV MA15 infection (Fig. 1A), as is oeftn observed in our mapping crosses (Schafer et al., 2022, Smith et al., 2016, Gralinski et al., 2017) (). F2 mice infected with SARS-CoV MA15 lost an average of 5% (ranging from a 7% gain to 26% loss) of their body weight, with congestion scores between 0-4 (median = 0.5). F2 mice infected with SARS-CoV-2 MA10 lost an average of 6% (ranging from 33% gain to 28% loss) of their body weight, with congestion score s between 0-4 (median = 0.5). F2 mice infected with HKU3-CoV MA exhibited less severe weight loss and congestion scores compared to those infected with SARS-CoV MA15 and SARS-CoV-2 MA10. There was still a substantial range of disease responses aeftr HKU3 -CoV MA infection, with mice losing an average of 1% (ranging from 7% gain to 13% loss) of their body weight by day 4 and congestion scores ranging from 0-2 (median = 0.5). These results highlight the value of our mouse-adapted viruses, SARS-CoV MA15 and SARS-CoV-2 MA10, in leading to highly correlated parameters of disease manifestation . The evaluation of coronavirus-induced disease across three diefrent vi ruses indicates that there might be host genetic mechanisms that lead to common disease responses despite genetic diefrences

across coronaviruses, and thus increases the impact of the nfidings to potentially encompass future viral epidemics. CC006xCC044 F2 mice. (A) Weight loss in n=391 F2 mice aeftr infection with SARS -CoV MA15. (B) Weight loss in n=274 F2 mice aeftr infection with SARS

-CoV-2 MA10. (C) Weight loss in n=90 F2 mice aeftr 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 scores in F2 mice, colored by infection group.

-CoV MA15 (see Fig. 1A). (D) Distribution of congestion

Concurrent with viral challenge, we genotyped these F2 mice on the miniMUGA array (Sigmon et al., 2020). We lfitered the 10,819 biallelic single nucleotide polymorphisms (SNPs) down to a set of 2,599 well-performing markers which segregated between CC006 and CC044 on the autosomes and X-chromosome. These markers were well-distributed across the genome, with a median and maximum distance between markers of 0.5 Mb and 50 Mb, respectively . Using this set of markers, we performed QTL mapping using R/qtl (Broman et al., 2003) in both the SARSCoV MA15- and SARS-CoV-2 MA10-infected mice. For each virus, mapping was performed on vfie phenotypes: weight on each of days 2-4 (with weight on day 0 as a covariate to control for baseline weight), an “area above the curve” (AAC) measure to capture the overall weight loss trajectory for each mouse, and congestion score . We idenetifd a total of seven loci associated with these aspects of coronavirus disease severity (Table 1), six signicfiant loci ( HrS43-48, P < 0.05) and 1 suggestive locus ( HrS49, P < 0.10).

immunological and antiviral processes and which have been shown to specicfially have a role during COVID-19 development and disease. Several chemokine receptors, like Ccr4, Ccr8, and Cx3cr1, are involved in shaping the specific immune (adaptive) responses during SARS -CoV-2 infection (Wang et al., 2022, Zhang et al., 2022, Zhou et al., 2021, Victor et al., 2022), while allelic variants (Cmtm8, Cspg5, Dbr1, Gnai2, and Mlh1) have been described to have functions in DNA splicing, stability, and maintenance during COVID-19 disease (Chen et al., 2021, Ariumi, 2022).

an exonuclease, two cellular genes, which are directly involved in the SARS-CoV-2 replication (Chen et al., 2021, Ariumi, 2022).

Here, we show that several disease phenotypes during SARS-CoV MA15, SARS-CoV-2 MA10 and HKU3-CoV MA infection in a CC006xCC044 F2 cross are associated with a locus (HrS43) which is also associated with SARS-CoV-2 disease outcome in humans. As such, this study is the rifst to conclusively demonstrate that sarbecovirus disease is, in part, controlled by common host loci, and that this control is relevant across mammalian hosts. Such conserved and broadly relevant loci are of high interest for global public health outcomes, as they point to mechanisms of susceptibility that can inform treatment and intervention strategies for current and future viral epidemics. Further, consistent associations across mouse and human studies demonstrate that susceptibility mechanisms are conserved across mammals and supports the use of mouse models in the study of host genetic response to viral infecotin . Altogether, our studies point to a set of host genes driving these outcomes across both human and mouse systems, suggest that future virus emergences can be putatively treated based on prior emergence analyses, and reinforce the utility of mammalian model systems to inform our und erstanding of emerging infections.

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