Wednesday, January 15, 2025
1/15/2025
The ongoing coronavirus disease-2019 (COVID-19) pandemic, caused by a novel coronavirus (CoV) termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is closely related to SARS-CoV, poses a grave threat to global health, and has devastated societies worldwide. One puzzling aspect of COVID-19 is the impressive variation in clinical manifestations among infected individuals, from a majority who are asymptomatic or exhibit mild symptoms to a smaller, largely age-dependent fraction who develop life-threatening conditions. Unfortunately, knowledge of the underlying biology behind COVID-19 susceptibility is woefully inadequate. Conceivably, some of the differences are likely the consequence of host genetic factors. Systems genetics using diverse and replicable cohorts of isogenic mice represents a powerful way to dissect those host genetic differences that modulate microbial infections. We have recently demonstrated that the two founders of the large BXD family of mice — C57BL/6J (B6) and DBA/2J (D2), differ substantially in their susceptibility to a mouse- adapted SARS-CoV, MA15. Following intranasal challenge, D2 develop a more severe disease and support more prolonged pulmonary viral replication than B6. In preliminary studies, we have observed a similar phenomenon when comparing aged B6 and D2 mice for infection by a mouse-adapted SARS-CoV-2 virus, CMA4. These key findings support the practicality of using the BXD family of mice to systemically dissect virus- host interactions that modulate sensitivity to and disease progression of SARS-CoV or SARS-CoV-2 infection. We hypothesize that variations in host genetic makeup regulate the host responses to SARS-CoV-2 infection, thereby imparting differing susceptibility/resistance to and outcome of COVID-19. Two specific aims are proposed to test this hypothesis. In Aim 1, we will determine the impact of genetic background on SARS-CoV-2 infection in the parental strains and across a subset of ~30 BXDs. We will first define the various phenotypes associated with disease severity, pathogen load, and innate immune responses that distinguish between aged B6 and D2 following infection with SARS-CoV-2 CMA4 and B.1.351 (a SARS-CoV-2 patient isolate capable of replication in wild-type mice), respectively. We will then characterize these measurable disease-state phenotypes, transcriptome and cytokine profiles across a cohort of aged BXD strains of diverse genotypes. In Aim 2, we will integrate the phenotypic and transcriptomic datasets from Aim 1 and combine them with the already acquired genotypes and sequence data for the BXD strains to map genetic loci and define the candidate genes and molecular networks that regulate SARS-CoV-2 replication and pathogenesis. Data from these studies will uncover novel insights into age-independent host genetic factors that modulate viral replication and disease susceptibility during SARS-CoV-2 infection. The new knowledge gained will aid the development of countermeasures against SARS-CoV-2 and possibly other pathogenic human CoV infections.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).