In a recent study posted to the bioRxiv* preprint server, the authors demonstrated that the sarbecovirus pathogenesis was regulated by a multitrait locus.
Study: A Multitrait Locus Regulates Sarbecovirus Pathogenesis. Image Credit: NIAID
Virus outbreaks are a constant challenge to economic stability and human health. Prior reports depict that infectious diseases influence the genetic structure of the human population, and genetic variation impacts vulnerability to a variety of viral illnesses. The specific alleles and genes that influence distinct illness outcomes in respiratory viral infections, on the other hand, are mostly unknown.
Further, traditional human genome-wide association studies (GWAS) methodologies for analyzing infectious outcomes have been difficult to adopt due to various obstacles. Mouse models of infectious diseases, on the contrary, offer experimental control and accuracy, making analytical and mechanistic investigations of the influence of genetic variation on infection easier.
About the study
In the present investigation, the scientists used a genetic mapping cross among two diverse Collaborative Cross (CC) mouse sequences to investigate disease outcomes of severe acute respiratory syndrome coronavirus (SARS-CoV) infections. The team used the CC model to assess the genetic vulnerability pattern of sarbecovirus infections in mice.
The researchers employed their SARS-CoV MA15 model, which outlines many disease outcomes noted in humans, to study female mice groups from five distinct CC strains exposed to 2003 SARS-CoV. Hence, broadening the prior comprehension of how genetic variation leads to variable SARS-CoV outcomes. They created a large F2 intercross among CC074 and CC011 mice to determine the genetic background of SARS-CoV pathogenesis and tracked illness outcomes.
At nine to 12 weeks of age, F2 mice were injected intranasally using a 1x104 plaque-forming unit (PFU) of SARS-CoV MA15. In addition to conventional SARS-CoV-related characteristics, such as viral burden, weight loss, lung congestion, and death, the team evaluated circulating immune cells and lung function to widen the knowledge of the reaction to SARS-CoV infection.
The SARS-CoV-2 MA10 strain, which has many CoV disease 2019 (COVID-19) disease characteristics reported in human patients, was used to infect CC074 and CC011. The scientists investigated the changes in sequence among CC074 and CC011 in the conserved synteny region of Chr3.
The team concentrated on CXCR6 and CCR9, which were variously expressed by the corresponding mouse strains, to investigate the influence of gene expression changes on virus illness phenotypes. To establish that the occurrence of a 129 haplotype at the chromosome 9 (Chr9) locus was not responsible for illness differences, they found three CC strains with a 129 haplotype at this locus (CC041, CC039, and CC065). Besides, the researchers analyzed the sensitivity to SARS-CoV-2 in these three strains compared to CC074 and CC011 mice.
Additionally, the authors monitored aged-matched and CXCR6-deficient control mice infected with SARS-CoV-MA15 and SARS-CoV-2 MA10 for a week because the Chr9 locus also had variants accumulating in CXCR6 that could contribute to lower gene expression and severe illness.
Findings and conclusions
The team discovered that multiple loci govern variable disease outcomes for a range of features in the setting of SARS-CoV infection. Significantly, the authors identified a mouse Chr9 locus that had preserved synteny with a human GWAS site for severe SARS-CoV-2 disease. This quantitative trait locus (QTL) exhibits preserved synteny towards a Chr3 human locus (3p21.31), discovered in the COVID-19 human GWAS, and predicts catastrophic outcomes and hospitalization.
The investigators followed up and confirmed a function for the Chr9 locus and discovered two potential genes, CXCR6 and CCR9, that both have a critical role in modulating the severity of SARS-CoV-2, SARS-CoV, and a distantly associated bat sarbecovirus illness outcomes. The CXCR6 and CCR9 genes were located inside the multitrait QTL situated on Chr9, possessing natural polymorphisms resulting in modified expression levels. The similar susceptibility characteristics of the CC074 and CC011 parent mouse lines and CXCR6 and CCR9 lacking mice infected with SARS-CoV-2 MA10, SARS-CoV MA15, or BtCoV HKU3-SRBD MA illustrate the role of human Chr3 locus in severe SARS-CoV-2 illness proneness throughout species and distinct sarbecoviruses, and showcasing the functionality of pre-emergence disease models.
Moreover, the current findings show that the CC mouse panel was ideal for identifying and validating pertinent susceptibility zones for additional human chronic and infectious diseases. In addition, it demonstrates that the CC mouse model serves as a focal point for a better comprehension of arising sarbecovirus disease trends in human and animal populations.
In conclusion, the present study established a template for identifying and characterizing multitrait loci that are responsible for deadly infectious outcomes between species using experimental mouse crosses.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- A Multitrait Locus Regulates Sarbecovirus Pathogenesis; Alexandra Schäfer, Sarah R. Leist, Lisa E. Gralinski, David R. Martinez, Emma S. Winkler, Kenichi Okuda, Padraig E. Hawkins, Kendra L Gully, Rachel L. Graham, D. Trevor Scobey, Timothy A. Bell, Pablo Hock, Ginger D. Shaw, Jennifer F. Loome, Emily A. Madden, Elizabeth Anderson, Victoria K. Baxter, Sharon A. Taft-Benz, Mark R. Zweigart, Samantha R. May, Stephanie Dong, Matthew Clark, Darla R. Miller, Rachel M Lynch, Mark T. Heise, Roland Tisch, Richard C. Boucher, Fernando Pardo Manuel de Villena, Stephanie A. Montgomery, Michael S. Diamond, Martin T. Ferris, Ralph S. Baric. bioRxiv preprint 2022. DOI: https://doi.org/10.1101/2022.06.01.494461, https://www.biorxiv.org/content/10.1101/2022.06.01.494461v1