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From friend to foe: proviral role of IRF-3 in chronic gammaherpesvirus infection

Award Number: R21AI182596
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: 01/19/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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From friend to foe: proviral role of IRF-3 in chronic gammaherpesvirus infection - Abstract Gammaherpesviruses establish life-long infections in >95% of adults worldwide and are associated with B cell lymphomas. Gammaherpesvirus-driven cancers develop in both immunocompromised and immunocompetent individuals; prevention of such cancers is currently impossible due to absence of vaccines, curative antivirals, and defined risk factors for lymphomagenesis. Manipulation of B cell differentiation lies at the heart of chronic gammaherpesvirus infection and pathogenesis. Specifically, gammaherpesviruses use natural proliferative capacity of germinal center B cells to amplify latent viral reservoir. Further, germinal center B cells are believed to be the target of viral transformation, as a majority of gammaherpesvirus-driven B cell lymphomas are germinal center-derived. Despite the importance of germinal center response for chronic infection and lymphomagenesis, very few factors that control infection of germinal center B cells have been defined. Interferon Regulatory Factor 3 (IRF-3) is a transcription factor that targets many cellular genes, including interferon (IFN) β. We discovered that, contrary to the predicted role of IRF-3 as an antiviral factor, IRF-3 supports latent gammaherpesvirus infection of germinal center B cells. The proposed studies test the hypothesis that IRF-3 is usurped by gammaherpesvirus to facilitate latent infection of germinal center B cells, with subsequent generation of memory B cells that host life-long latent viral reservoir. This is achieved through IRF-3-dependent regulation of cellular and viral target genes. Successful completion of the proposed studies will offer an insight into the mechanism by which the virus usurps a classical innate antiviral factor for the viral benefit.


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 = $191,148 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	2	12/4/2024	NON-COMPETING CONTINUATION	$191,148
														Subtotal = $191,148

Issue Date FY: 2024 ( Subtotal = $248,517 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	1/19/2024	NEW	$223,665
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	1	9/12/2024	NEW	$24,852
														Subtotal = $248,517

Grand Total All Awards = $439,665

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From friend to foe: proviral role of IRF-3 in chronic gammaherpesvirus infection

Award Number: R21AI182596

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: 01/19/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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