# Role of IRE1 Alpha in Coronavirus Infections

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $574,718

## Abstract

Project Summary
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a recently emergent, currently pandemic
virus and etiological agent of Coronavirus Induced Disease-19 (COVID-19). Despite a flood of scientific
investigation, critical gaps remain in our understanding of the basic cellular processes that facilitate replication
of coronaviruses, including SARS-CoV-2, and contribute to the pathogenesis of severe disease.
Our preliminary data demonstrate that IRE1α, a component of the cellular response to endoplasmic reticulum
(ER) stress, is required for SARS-CoV-2 replication and inflammatory cytokine responses. However, the
stage(s) of the viral life cycle and downstream cellular pathways that mediate these effects remain completely
unknown. ER stress and IRE1α activation are well-associated with conditions such as obesity, diabetes,
hypertension, and aging, all of which are risk factors for severe manifestations of COVID-19. We hypothesize
that comorbidity-associated ER stress primes both exuberant viral replication and pathogenic inflammatory
cytokine production via IRE1α. This project leverages our unique ability to test this hypothesis using cell
culture infection models, as well as specimens from patients with COVID-19. IRE1α inhibitors are under
evaluation for treatment of non-infectious human diseases, and we propose that this project will provide
preclinical evidence for the novel application of these drugs to treat infections with SARS-CoV-2 and potentially
other human coronaviruses.
The experiments outlined in this proposal will determine the molecular mechanism(s) by which IRE1α supports
SARS-CoV-2 infection. IRE1α is a nuclease which initiates nonconventional splicing of XBP1 mRNA, which
encodes a pleiotropic transcription factor. IRE1α also targets other specific RNAs leading to their degradation.
We will determine whether the requirement for IRE1α is XBP1-dependent or -independent and dissect the
downstream cellular processes that facilitate SARS-CoV-2 replication and inflammatory cytokine responses
(Aim 1). We will systematically identify stage(s) of the SARS-CoV-2 life cycle that require IRE1α (Aim 2). We
predict that IRE1α most likely supports biogenesis of ER-derived viral replication platforms, and will focus
experiments on this hypothesis. We predict that IRE1α represents a target for dual anti-viral and anti-
inflammatory therapy and will test this in mouse models of SARS-CoV-2 infection (Aim 3). Finally, we will
determine whether IRE1α activation occurs during human infection and ER stress is a prognostic marker for
severe COVID-19. Together, the results of this project will reveal basic cellular processes occurring during
coronavirus infection and host factors critical for the pathogenesis of COVID-19.
.

## Key facts

- **NIH application ID:** 10789885
- **Project number:** 5R01AI162684-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Susan Leilani Fink
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,718
- **Award type:** 5
- **Project period:** 2022-03-11 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789885

## Citation

> US National Institutes of Health, RePORTER application 10789885, Role of IRE1 Alpha in Coronavirus Infections (5R01AI162684-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10789885. Licensed CC0.

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