# Mechanistic characterization of SARS-CoV2 associated kidney injury

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $393,750

## Abstract

SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID-
19). Currently over 16.5 million people in the US have confirmed infection with SARS-CoV2 and over 300,000
have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ
dysfunction, with a significant portion of severe COVID patients developing acute kidney injury. 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 a predictor of severe COVID-19
disease. The mechanism by which the host restricts necroptosis is unclear. In 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. We have also shown that ISG15 deficient mice rapidly succumb
to ischemia-reperfusion injury of the kidney characterized by a massive release of proinflammatory cytokines.
In this proposal we will test the hypothesis that ISG15 serves as a critical host restriction factor in regulating
programmed necroptosis and downstream inflammatory responses within the kidney to limit acute kidney injury
during SARS-CoV2 infection. We will utilize kidney organoids derived from induce pluripotent stem cells in which
ISG15 has been deleted by CRISPR, a co-culture system with kidney organoids and primary tracheal epithelial
cultures (hTECs), and in vivo mouse model of SARS-CoV-2 to ask several questions including: 1) Does SARS-
CoV2 induce damage to kidney epithelial cells via direct viral transduction or in response to systemic
inflammation?; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine
production in kidney epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by
ISG15 contribute to acute kidney injury during SARS-CoV2 infection? Overall, our studies will provide important
insight into host factors that restrict necroptosis and could be an important contributor to severe COVID-19
induced kidney injury.

## Key facts

- **NIH application ID:** 10427448
- **Project number:** 5R01DK130476-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Deborah J Lenschow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2021-06-11 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427448

## Citation

> US National Institutes of Health, RePORTER application 10427448, Mechanistic characterization of SARS-CoV2 associated kidney injury (5R01DK130476-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427448. Licensed CC0.

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