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Mechanism, Function, and Exploitation of Influenza A Virus-Activated Cell Death

Award Number: R01AI135025
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: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Mechanism, Function, and Exploitation of Influenza A Virus-Activated Cell Death - PROJECT SUMMARY/ABSTRACT Influenza A virus (IAV) triggers the death of most cell types in which it replicates, both in culture and in vivo. In 2016, we described an IAV-activated cell death pathway which accounts for almost all IAV-activated death in infected pulmonary cells. Over that past funding cycle, we showed that this pathway is initiated when the host sensor protein ZBP1 detects viral Z-RNAs and activates RIPK3 kinase. RIPK3 then triggers parallel, redundant pathways of programmed necrosis (necroptosis) and apoptosis. These studies have outlined the dominant cell death pathway activated by IAV in infected lungs. They have also demonstrated that ZBP1 is an RNA sensing protein, and that the RNA structures it recognizes are Z-RNAs, which are unique, left-handed double-helical RNA species that had not previously been thought to occur in nature. We have now made several intriguing new discoveries that set the stage for this application. First, we found that the Z-RNAs produced during IAV infections are not just viral in origin, but host cell-derived as well. Second, we observed that in alveolar macrophages (AMs), unlike in all other lung cell types tested, ZBP1 activation does not result in cell death, but instead in a non-cytolytic transcriptional program essential for protection against IAV lethality. Third, we found that necroptosis during IAV infections is activated not in the cytoplasm, but in the nucleus, resulting in nuclear rupture. Such `nuclear necroptosis' is highly inflammatory, and is a major driver of the pathogenesis during severe influenza. Finally, we have obtained important new insight into the coevolution of IAV with the necroptosis machinery in birds and bats, the two major natural hosts of these viruses. While birds simply do not express ZBP1, we have found that bats possess a single amino acid alteration in RIPK3 which selectively abrogates necroptosis (but not apoptosis) signaling, potentially explaining how these organisms tolerate such a large diversity of IAV subtypes. To our knowledge, these discoveries provide the first evidence that endogenous Z-RNAs may function as innate ligands for ZBP1 in anti-IAV immunity, that ZBP1 has non-cytolytic functions during IAV infections, and that a IAV activates a unique, hyper-inflammatory form of necroptosis from the nucleus. They also provide fresh evolutionary insight into how IAV strains are tolerated in their natural reservoirs, but can activate pathogenic necroptosis in humans. Based these and other observations, the goals of this proposal are to (1) to identify and characterize endogenous Z-RNA ligands for ZBP1, and to determine their importance to ZBP1 activated cell death in IAV-infected cells; (2) to delineate the mechanism and function of non-cytolytic ZBP1 signaling in AMs; and (3) to understand the role of nuclear necroptosis in influenza pathogenesis and in evolution. These studies unite two labs with expertise in ZBP1 signaling (Balachandran) and IAV pathogenesis (Thomas), and their successful completion stands to provide pioneering insight into the mechanism and function of ZBP1-initiated cell death during IAV infections, with important clinical and evolutionary ramifications.


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 = $1,460,069 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	9	8/28/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,460,069
2025	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	8/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,460,069

Issue Date FY: 2024 ( Subtotal = $720,326 )
2024	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	8	8/6/2024	NON-COMPETING CONTINUATION	$720,326
2024	2022	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	1/2/2024	COMPETING CONTINUATION	$6,862
2024	2021	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	1/2/2024	NON-COMPETING CONTINUATION	-$6,862
														Subtotal = $720,326

Issue Date FY: 2023 ( Subtotal = $720,326 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	7	8/9/2023	NON-COMPETING CONTINUATION	$720,326
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	7	9/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $720,326

Issue Date FY: 2022 ( Subtotal = $742,326 )
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	6	4/15/2022	COMPETING CONTINUATION	$742,326
														Subtotal = $742,326

Issue Date FY: 2021 ( Subtotal = $577,887 )
2021	2021	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	8/4/2021	NON-COMPETING CONTINUATION	$577,887
														Subtotal = $577,887

Issue Date FY: 2020 ( Subtotal = $667,142 )
2020	2020	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	8/26/2020	NON-COMPETING CONTINUATION	$667,142
														Subtotal = $667,142

Issue Date FY: 2019 ( Subtotal = $667,142 )
2019	2019	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	8/9/2019	NON-COMPETING CONTINUATION	$667,142
														Subtotal = $667,142

Issue Date FY: 2018 ( Subtotal = $676,077 )
2018	2018	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	8/10/2018	NON-COMPETING CONTINUATION	$676,077
														Subtotal = $676,077

Issue Date FY: 2017 ( Subtotal = $565,577 )
2017	2017	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	9/22/2017	NEW	$565,577
														Subtotal = $565,577

Grand Total All Awards = $6,796,872

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Mechanism, Function, and Exploitation of Influenza A Virus-Activated Cell Death

Award Number: R01AI135025

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: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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