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Mechanisms of innate resistance to virus infections

Award Number: R01AI130110
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: 02/01/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2027
AWARD TERMINATION DATE: 04/21/2025

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Mechanisms of innate resistance to virus infections - SUMMARY Cardiac dysfunction is among the most common extrapulmonary complications of severe influenza virus infections. Although the heart complications of influenza virus infection are a clearly recognized clinical problem, they are poorly studied in terms of pathogenic mechanisms. We lack basic scientific understanding of 1) whether influenza virus directly or indirectly causes heart damage, 2) what viral features facilitate cardiac tropism of certain strains, 3) how virus disseminates from the lung specifically to the heart in the absence of viremia, and 4) how the immune system influences heart pathogenesis. The major barrier to mechanistic research in this area has been the lack of tractable animal models that recapitulate significant cardiac dysfunction in severe influenza. We have overcome this obstacle by developing interferon-induced transmembrane protein 3 (IFITM3) KO mice as a model of severe influenza virus infection that includes viral replication in the heart and significant cardiac electrical dysfunction, inflammation, and fibrosis. Importantly, IFITM3 is an antiviral protein of the innate immune system in which common deficiencies in the human population render individuals more susceptible to severe infections, making IFITM3 KO mice a relevant and informative model. We will make use of this groundbreaking model in the following three Aims. In Aim 1, we will determine whether virus dissemination and replication directly in heart tissue is required for this pathology or whether influenza virus indirectly induces heart dysfunction through systemic inflammation from the severely infected lung. To address this fundamental controversy in the field, we have developed a novel and innovative recombinant influenza virus strain with specific inability to replicate in heart cells while being fully replicative in the lung. In Aim 2, we will identify viral features that endow specific virus strains with cardiac tropism by using a candidate viral gene approach with reassortant viruses, as well as an adaptive passaging approach. In Aim 3, we will solve the mystery of how influenza virus moves specifically from the lung to the heart in the absence of viremia and other organ infections. For this, we will test whether infection of migratory immune cells facilitates virus trafficking to the heart. We will further investigate how IFITM3 expression in hematopoietic immune cells influences cardiac dissemination of virus and cardiac dysfunction during infection. Overall, our research will answer fundamental questions in the influenza field, and will reveal new strategies for combatting influenza-associated cardiac dysfunction.


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: 2026 ( Subtotal = $430,396 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	10	1/13/2026	NON-COMPETING CONTINUATION	$430,396
														Subtotal = $430,396

Issue Date FY: 2025 ( Subtotal = $438,704 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	9	1/15/2025	NON-COMPETING CONTINUATION	$438,704
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	8	4/21/2025	TERMINATION	$0
														Subtotal = $438,704

Issue Date FY: 2024 ( Subtotal = $532,319 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	004	8	5/28/2024	NON-COMPETING CONTINUATION	$44,676
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	8	1/12/2024	NON-COMPETING CONTINUATION	$402,100
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	8	1/16/2024	SUPPLEMENT FOR EXPANSION	$85,543
2024	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	003	6	1/25/2024	COMPETING CONTINUATION	$164,868
2024	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	5	1/25/2024	NON-COMPETING CONTINUATION	-$164,868
														Subtotal = $532,319

Issue Date FY: 2023 ( Subtotal = $503,647 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	7	8/16/2023	SUPPLEMENT FOR EXPANSION	$43,560
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	7	1/10/2023	NON-COMPETING CONTINUATION	$460,087
														Subtotal = $503,647

Issue Date FY: 2022 ( Subtotal = $471,166 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	6	11/22/2021	COMPETING CONTINUATION	$471,166
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	6	12/9/2021	COMPETING CONTINUATION	$0
														Subtotal = $471,166

Issue Date FY: 2021 ( Subtotal = $377,709 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	1/8/2021	NON-COMPETING CONTINUATION	$377,709
														Subtotal = $377,709

Issue Date FY: 2020 ( Subtotal = $378,405 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	1/10/2020	NON-COMPETING CONTINUATION	$378,405
														Subtotal = $378,405

Issue Date FY: 2019 ( Subtotal = $379,061 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	3	1/10/2019	NON-COMPETING CONTINUATION	$379,061
														Subtotal = $379,061

Issue Date FY: 2018 ( Subtotal = $378,715 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	1/8/2018	NON-COMPETING CONTINUATION	$378,715
														Subtotal = $378,715

Issue Date FY: 2017 ( Subtotal = $376,969 )
2017	2017	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	1/26/2017	NEW	$376,969
														Subtotal = $376,969

Grand Total All Awards = $4,267,091

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Mechanisms of innate resistance to virus infections

Award Number: R01AI130110

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: 02/01/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2027

AWARD TERMINATION DATE: 04/21/2025

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