Study: A Multitrait Locus Regulates Sarbecovirus Pathogenesis. Image Credit: NIAID

Pathogenesis of Sarbecovirus regulated by a multitrait locus

In a recent study published on bioRxiv* preprint server, the authors demonstrated that sarbecovirus pathogenesis is regulated by a multi-trait locus.

​​​​​​​Study: A multitrait locus regulates the pathogenesis of Sarbecovirus. ​​​​​​Image credit: NIAID

Background

Virus outbreaks are a constant challenge to economic stability and human health. Previous reports show that infectious diseases influence the genetic structure of the human population and that genetic variation impacts susceptibility to various viral diseases. The specific alleles and genes that influence different disease outcomes in viral respiratory infections, on the other hand, are mostly unknown.

Furthermore, traditional human genome-wide association studies (GWAS) methodologies for the analysis of infectious outcomes have been difficult to adopt due to various obstacles. Mouse models of infectious diseases, on the contrary, offer experimental control and precision, which facilitates analytical and mechanistic investigations of the influence of genetic variation on infection.

About the study

In the present investigation, scientists used a genetic mapping cross between two diverse Collaborative Cross (CC) mouse sequences to study the 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 used their SARS-CoV MA15 model, which describes many of the disease outcomes noted in humans, to study groups of female mice of five distinct CC strains exposed to SARS-CoV 2003. Therefore, expanding understanding prior of how genetic variation leads to variable SARS-CoV outcomes. They created a large F2 cross between CC074 and CC011 mice to determine the genetic background of SARS-CoV pathogenesis and track disease outcomes.

At 9–12 weeks of age, F2 mice were injected intranasally using a 1×104 plaque-forming unit (PFU) of SARS-CoV MA15. In addition to conventional SARS-CoV-related features, such as viral load, weight loss, lung congestion and death, the team assessed circulating immune cells and lung function to expand knowledge of the response to SARS-CoV infection.

SARS-CoV-2 strain MA10, which exhibits many of the features of CoV disease 2019 (COVID-19) reported in human patients, was used to infect CC074 and CC011. Scientists investigated sequence changes between CC074 and CC011 in the conserved syntenic region of Chr3.

The team focused on CXCR6 and CCR9, which were variously expressed by the corresponding mouse strains, to investigate the influence of gene expression changes on viral disease phenotypes. To establish that the presence of a 129 haplotype at the chromosome 9 (Chr9) locus was not responsible for the disease differences, they found three CC strains with a 129 haplotype at this locus (CC041, CC039 and CC065). In addition, the researchers analyzed the susceptibility to SARS-CoV-2 in these three strains compared to CC074 and CC011 mice.

Additionally, the authors monitored age-matched CXCR6-deficient control mice infected with SARS-CoV-MA15 and SARS-CoV-2 MA10 for one week, as the Chr9 locus also showed accumulating variants. in CXCR6 that could contribute to lower gene expression and severe effects. diseases.

Findings and Conclusions

The team found that multiple loci govern variable disease outcomes for a range of characteristics in the setting of SARS-CoV infection. Significantly, the authors identified a mouse Chr9 locus that retained synteny with a human GWAS site for severe SARS-CoV-2 disease. This quantitative trait locus (QTL) exhibits preserved synteny to a human Chr3 locus (3p21.31), discovered in human COVID-19 GWAS, and predicts catastrophic outcomes and hospitalization.

The researchers tracked and confirmed a function for the Chr9 locus and discovered two potential genes, CXCR6 and CCR9, both of which have critical roles in modulating the severity of SARS-CoV-2, SARS-CoV, and a remotely associated bat sarbecovirus disease results. The CXCR6 and CCR9 genes were located within the multi-trait QTL located on Chr9, possessing natural polymorphisms resulting in altered expression levels. The similar susceptibility characteristics of parental mouse lines CC074 and CC011 and mice lacking CXCR6 and CCR9 infected with SARS-CoV-2 MA10, SARS-CoV MA15 or BtCoV HKU3-SRBD MA illustrate the role of the human Chr3 locus in severe SARS-CoV-2 disease susceptibility among distinct species and sarbecoviruses, and highlighting the functionality of pre-emergence disease models.

Additionally, the current results show that the CC mouse panel was ideal for identifying and validating areas of susceptibility relevant to other chronic and infectious human diseases. Furthermore, it demonstrates that the CC mouse model serves as a focal point for a better understanding of sarbecovirus disease trends in human and animal populations.

In conclusion, the present study established a model to identify and characterize multi-trait loci that are responsible for lethal infectious outcomes across species using experimental mouse crosses.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

  • A multi-trait locus regulates the pathogenesis of Sarbecovirus; 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 2022 preprint. DOI: https://doi.org/10.1101/2022.06.01.494461, https://www.biorxiv.org/content/10.1101/2022.06.01.494461v1

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