# In vivo functional risk assessment of patient-specific genetic variants for severe COVID-19

> **NIH NIH U42** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $442,093

## Abstract

In vivo functional risk assessment of patient-specific genetic variants for severe COVID-19
 ABSTRACT & SCOPE OF WORK
The Mutant Mouse Resource and Research Center at the University of California, Davis (MMRRC-UC Davis)
is pleased to submit this administrative supplement for up to 1 year of support in response to ORIP's
participation in PA-20-272, “Administrative Supplements to Existing NIH Grants and Cooperative Agreements”
specifically related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and
coronavirus disease 2019 (COVID-19). This application addresses all three themes of the Call, including to (1)
investigate pathogenic coronaviruses, particularly SARS-CoV-2 and its viral variants, (2) gain a better
understanding of viral natural history, pathogenicity, and transmission, and (3) aid development of medical
countermeasures and suitable animal models for pre-clinical testing of enhanced vaccines and therapeutics for
acute and Post-Acute Sequelae of COVID-19. Specifically, an objective of the proposed project is to develop
and characterize new animal models by assessing host-specific characteristics and parameters that increase
risk of acute disease. Another objective of this project is to study the susceptibility of new humanized animals
to SARS-CoV-2 variants of concerns, with a special emphasis on the effect of genetic background on viral
susceptibility and pathogenesis. Therefore, this proposal will seek to investigate and gain a better
understanding of host-specific genetic effects on SARS-CoV-2 infection susceptibility and COVID-19 disease
risk. We hypothesize that humanized mouse models can accelerate determination of pathogenicity of patient-
specific genetic variants identified by GWAS as being associated with higher susceptibility to infection and/or
greater risk of disease after SARS-CoV-2 challenge. This project will build upon our successful efforts to
generate humanized knockin/murine knockout mouse lines for several genes (ACE2, TMPRSS2, and FURIN)
involved in SARS-CoV-2 binding, entry, and activation. With this prior experience in hand, we now propose to
1) use CRISPR/Cas9 in C57BL/6J;ACE2/TMPRSS2 mice to introduce 5 high risk genetic coding and
noncoding single nucleotide polymorphisms (SNPs) in genes regulating interferon signaling (Ifna10 and
Plscr1), immunological and inflammatory response (Tyk2 and Ppp1r15a), and substrate-specific cell
membrane transporter proteins (Slc6a20) shown by GWAS to be associated with increased illness; 2)
challenge and establish infection in male and female humanized SNP and control mice with SARS-CoV-2
(delta variant) under ABSL-3 conditions, and 3) assess in vivo infection rate, viral burden, body weight,
malaise, pulmonary function (µCT), and recovery of humanized SNP mice from acute disease. We will also
assess the severity of pulmonary disease using gross necropsy and quantitative histopathology. The outcome
of this research will be evidence that mouse models of p...

## Key facts

- **NIH application ID:** 10596847
- **Project number:** 3U42OD012210-23S3
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** KC KENT LLOYD
- **Activity code:** U42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,093
- **Award type:** 3
- **Project period:** 1999-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596847

## Citation

> US National Institutes of Health, RePORTER application 10596847, In vivo functional risk assessment of patient-specific genetic variants for severe COVID-19 (3U42OD012210-23S3). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10596847. Licensed CC0.

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