Tuesday, July 1, 2025 7/1/2025

Role of IRE1 Alpha in Coronavirus Infections

Award Number: R01AI162684
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/11/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

Group Awards By:

View Award Description

Role of IRE1 Alpha in Coronavirus Infections - 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. .


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $557,476 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	4	2/13/2025	NON-COMPETING CONTINUATION	$557,476
														Subtotal = $557,476

Issue Date FY: 2024 ( Subtotal = $574,718 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	3	2/21/2024	NON-COMPETING CONTINUATION	$517,247
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$57,471
														Subtotal = $574,718

Issue Date FY: 2023 ( Subtotal = $544,713 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	2	2/16/2023	NON-COMPETING CONTINUATION	$544,713
														Subtotal = $544,713

Issue Date FY: 2022 ( Subtotal = $544,713 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	1	3/11/2022	NEW	$544,713
														Subtotal = $544,713

Grand Total All Awards = $2,221,620

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of IRE1 Alpha in Coronavirus Infections

Award Number: R01AI162684

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/11/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer