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Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus

Award Number: R01AI155539
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: 05/10/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus - Human cytomegalovirus (HCMV) establishes a life-long persistent infection by evading the immune system, in part, by direct cell-to-cell viral spread. In solid organ or stem cell transplant recipients, HCMV spread leads to end-organ diseases that can cause death. During pregnancy, HCMV spread causes congenital infection and is a leading cause of congenital disabilities. No HCMV treatment offers a cure, and there is no vaccine. Thus, there is a need for new treatments to limit infection based on novel discoveries in HCMV biology. Viral proteins required for HCMV cell-to-cell spread are known, but the host processes involved in HCMV cell-to-cell spread have received less attention. Clinical strains of HCMV spread most efficiently through cell-to-cell means, but the molecular mechanisms—including host metabolic ones—essential to HCMV cell-to-cell spread are largely unknown. Understanding host mechanisms regulating cell-to-cell spread may lead to new understandings of how to reduce HCMV infection. Our research has uncovered a novel role of metabolite signaling in promoting HCMV spread. This project's overall goal is to mechanistically understand virus-host interactions regulating metabolite signaling essential to HCMV cell-to-cell spread. We found a metabolite in tryptophan metabolism—kynurenine (KYN)—enhances HCMV spread. In addition to its metabolic role, KYN is a signaling messenger. KYN signals through aryl hydrocarbon receptor (AhR). We show that activation of AhR supports HCMV replication. Moreover, we found that hypoxia-inducible factor 1α (HIF1α), through its metabolic regulatory function, limits the production of KYN and suppresses HCMV infection. We hypothesize that metabolite-mediated signaling from infected cells to uninfected cells promotes HCMV cell-to-cell spread, which is attenuated by a HIF1α-dependent cellular response. The proposed research will determine molecular mechanisms involved in the enhancement of HCMV infection by KYN-metabolite signaling (aim 1) and define virus-host interactions regulating HIF1α attenuation of HCMV cell-to-cell spread (aim 2). The experimental approach will integrate virus assays, CRISPR/Cas9 engineering, and untargeted metabolomics to understand HCMV biology. Our findings will provide a mechanistic understanding of metabolite signaling and AhR activity in promoting HCMV cell-to-cell spread and the HIF1α-dependent host-response that targets metabolite signaling to reduce infection. Our studies will advance our knowledge in an understudied area of HCMV research that will provide significant steps-forward in developing novel strategies to treat HCMV infection and limit HCMV-related disease.


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 = $0 )
2026	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	5	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $366,372 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	5	4/25/2025	NON-COMPETING CONTINUATION	$366,372
														Subtotal = $366,372

Issue Date FY: 2024 ( Subtotal = $367,659 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	4	4/15/2024	NON-COMPETING CONTINUATION	$367,659
														Subtotal = $367,659

Issue Date FY: 2023 ( Subtotal = $368,851 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	3	4/25/2023	NON-COMPETING CONTINUATION	$368,851
														Subtotal = $368,851

Issue Date FY: 2022 ( Subtotal = $369,954 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	2	4/20/2022	NON-COMPETING CONTINUATION	$369,954
														Subtotal = $369,954

Issue Date FY: 2021 ( Subtotal = $370,976 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	1	5/10/2021	NEW	$370,976
														Subtotal = $370,976

Grand Total All Awards = $1,843,812

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Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus

Award Number: R01AI155539

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: 05/10/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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