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The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function

Award Number: R01AI171408
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: 08/19/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function - The pivotal discovery of RNA viruses, like the bi-segmented, single-stranded arenavirus family, producing defective interfering particles (DIPs) over 50 years ago prompted investigations on their contribution to viral pathogenesis and host immunity. However, many basic questions remain, including the molecular basis for how DIPs are regulated and the contribution of DIPs to virus–host interactions, including the persistence of zoonotic pathogens in their reservoir host. Our overall goal is to identify the cellular machinery responsible for regulating arenavirus DIP production and interrogate the impact DIPs have on reservoir fitness. A major constraint to understanding the true role of DIPs in viral pathogenesis and disease ecology is the lack of tools to modulate DIP levels in experimental systems. We recently discovered that LCMV uses divergent cellular pathways to produce standard virus particles versus DIPs. Using reverse genetic systems, we identified powerful host-driven post-translational modifications (PTMs) that dynamically regulate the production of infectious versus defective viral particles. These studies enabled us to engineer, for the first time, recombinant arenaviruses that no long produce DIPs. Our specific objectives will be to use these innovative approaches and tools to 1) define the mechanism by which host tyrosine kinases and NEDD4 Family E3 ubiquitin ligases regulate DIP formation and function, 2) expand our global map of arenavirus PTMs that may influence DIP production, and 3) connect these molecular findings to pathogenesis studies modeling both persistent infection of the rodent reservoir and acute infection of the rodent or incidental human host. Most RNA viruses that infect animals produce DIPs, which suggests they are fundamentally important for the maintenance of these viruses in nature. Our findings will be broadly applicable beyond the Bunyavirales order. Collectively, the completion of these studies will provide greater resolution on the regulation of DIP production and answer, for the first time, the role of DIP in viral persistence.


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 = $598,271 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	4	8/21/2025	NON-COMPETING CONTINUATION	$598,271
														Subtotal = $598,271

Issue Date FY: 2024 ( Subtotal = $613,623 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	3	7/16/2024	NON-COMPETING CONTINUATION	$613,623
														Subtotal = $613,623

Issue Date FY: 2023 ( Subtotal = $540,864 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	7/22/2023	NON-COMPETING CONTINUATION	$540,864
														Subtotal = $540,864

Issue Date FY: 2022 ( Subtotal = $543,938 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	1	8/19/2022	NEW	$543,938
														Subtotal = $543,938

Grand Total All Awards = $2,296,696

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The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function

Award Number: R01AI171408

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: 08/19/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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