# Host genetic determinants regulating susceptibility/resistance to SARS-CoV-2

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $231,000

## Abstract

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
count...

## Key facts

- **NIH application ID:** 10510620
- **Project number:** 1R21AI171779-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** KUI LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,000
- **Award type:** 1
- **Project period:** 2022-05-20 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510620

## Citation

> US National Institutes of Health, RePORTER application 10510620, Host genetic determinants regulating susceptibility/resistance to SARS-CoV-2 (1R21AI171779-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10510620. Licensed CC0.

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