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Overriding the Immune Evasion Tactics of Coronavirus

Award Number: R01AI158552
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: 08/12/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Overriding the Immune Evasion Tactics of Coronavirus - PROJECT SUMMARY/ABSTRACT Progression of SARS-Coronavirus-2 (SARS-CoV-2) infected patients to life threatening disease may result from a virus-mediated, dysregulated immune response associated with excessive production of inflammatory cytokines, cytokine release syndrome. In this proposal we seek to identify therapeutics and knowledge of Coronaviruses that will counteract the disruption in cytokine signaling pathways involved in effective host defense. We contribute to the urgent need for therapeutics that inhibit SARS-CoV-2 infection using pathway specific reporter cells to screen for therapeutically active compounds that restore cytokine signaling. Our pathway specific screens are a component in SBP-wide initiative to develop therapeutics that limit severe COVID-19. Our screening strategy selects drugs identified in libraries of pharmacologically active therapeutics that block SARS- CoV-2 lytic replication. We use cytokine pathway reporters to test these compounds in SARS-CoV-2 infection of a lung cell line and human lung organoids in BSL3 facilities. The selected candidates will undergo analysis for potential drug development. Fundamental knowledge of cytokine-regulated defense mechanisms related to Coronavirus infection limits the rational design of therapeutics and vaccines. To advance this knowledge we focus on the Lymphotoxin- β Receptor (LTβR) and the Herpesvirus entry mediator (HVEM, TNFRSF14) pathways known to regulate anti- viral cytokines, interferons (IFN) and interleukin-1(IL1β). Together, the LTβR and HVEM pathways act as an integrated, homeostatic network that inhibits virus replication yet limits tissue damaging cytokines. Two SARS- CoV-2 proteins, the Papain-like protease (PLPro, Nsp3) and Nsp9 target novel components in the TRAF3 interactome that control the NFκB transcriptome. We will determine the role of these components in the key cytokine pathways using genetic and pharmacologic approaches in a mouse coronavirus lung infection model. Together these two independent but complementary aims will provide an opportunity to help solve the SARS- CoV-2 pandemic, and protect future generations.


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 = -$6,096 )
2026	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	2/4/2026	SUPPLEMENT FOR EXPANSION	-$6,096
														Subtotal = -$6,096

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	7/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $601,563 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	4	7/30/2024	SUPPLEMENT FOR EXPANSION	$601,563
2024	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	7/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $601,563

Issue Date FY: 2023 ( Subtotal = $601,563 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	5/25/2023	NON-COMPETING CONTINUATION	$601,563
														Subtotal = $601,563

Issue Date FY: 2022 ( Subtotal = $601,563 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	7/26/2022	NON-COMPETING CONTINUATION	$601,563
														Subtotal = $601,563

Issue Date FY: 2021 ( Subtotal = $617,996 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	7/20/2021	NON-COMPETING CONTINUATION	$617,996
														Subtotal = $617,996

Issue Date FY: 2020 ( Subtotal = $617,996 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	8/12/2020	NEW	$617,996
														Subtotal = $617,996

Grand Total All Awards = $3,034,585

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Overriding the Immune Evasion Tactics of Coronavirus

Award Number: R01AI158552

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: 08/12/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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