# Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $236,250

## Abstract

SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease
2019 (COVID-19). Currently over 7.4 million people in the US have confirmed infection with
SARS-CoV2 and over 215,000 have died. Severe COVID-19 is characterized by pulmonary and
systemic inflammation and multi-organ dysfunction, which disproportionally affects elderly
patients. The mechanism by which SARS-CoV2 triggers such severe pathogenesis is poorly
understood. Recent clinical studies have suggested that cell death, especially the induction of
necroptosis, may be predictor of severe COVID-19 disease. The mechanism by which the host
restricts necroptosis is unclear. In the preliminary data we have shown that the interferon induced
protein, ISG15, acts as a negative regulator of necroptosis and its downstream inflammatory
responses during viral infection. In this proposal we will test the hypothesis that SARS-CoV2
induces necroptosis and that ISG15 functions as a negative regulator of necroptosis in respiratory
epithelial cells. We will use in vitro primary tracheal epithelial cultures (hTECs) and an in vivo
mouse adapted SARS-CoV2 animal model to ask several questions including: 1) Does SARS-
CoV2 induce necroptosis in respiratory epithelial cells; 2) Does ISG15 modulate necroptotic cell
death as well as proinflammatory cytokine/chemokine production in respiratory epithelial cells
during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to
SARS-CoV2 pathogenesis? Overall, our studies will provide important insight into the
pathogenesis of SARS-CoV2 infection and provide potential insight into mechanisms underlying
severe disease, which may direct efforts toward the development of diagnostic markers and future
countermeasures.

## Key facts

- **NIH application ID:** 10424558
- **Project number:** 5R21AI163822-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Deborah J Lenschow
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,250
- **Award type:** 5
- **Project period:** 2021-06-08 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424558

## Citation

> US National Institutes of Health, RePORTER application 10424558, Regulation of Cell Death and Inflammation by ISG15 during SARS-CoV2 Infection (5R21AI163822-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10424558. Licensed CC0.

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