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Modification of Host Chemokine Responses by Human Cytomegalovirus

Award Number: R15AI111232
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: 05/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2019

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Modification of Host Chemokine Responses by Human Cytomegalovirus - DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a member of the Herpesviridae family that manipulates the host immune system and establishes life-long latent infection. This successful co-existence with the host is mediated by the production of viral proteins that mimic normal immune modulators like cytokines, chemokines, and chemokine receptors. HCMV encodes four proteins with similarity to human chemokine receptors, US27, US28, UL33, and UL78. US28 and UL33 both exhibit ligand-independent constitutive signaling activity, and US28 has also been shown to signal in response to cellular chemokines. In contrast, no ligands or signaling outcomes have been identified for US27, and it remains an orphan receptor. A stable cell line expressing US27 was developed previously in order to screen for possible chemokine ligands for US27. While no ligands were identified, we made the unexpected observation that US27 significantly enhanced the signaling of a human chemokine receptor, CXCR4, in response to its natural ligand, CXCL12/SDF-1?. One of the many important physiological roles of CXCR4 involves directing immune cells to the bone marrow, which is the primary site of HCMV latency. Potentiation of CXCR4 signaling by US27 could represent a strategy by which HCMV targets virus-infected cells to the bone marrow in order to initiate a new round of infection and expand the reservoir of latently infected cells. The specific hypothesis being tested is that US27 forms heteromers with CXCR4 that stimulate increased movement of infected cells toward the chemokine CXCL12/SDF-1?. This hypothesis is supported by strong preliminary data demonstrating that cells expressing both US27 and CXCR4 exhibit greater calcium mobilization and enhanced chemotaxis in response to CXCL12/SDF-1? than controls. In addition, US27 and CXCR4 were found to co-localize to discrete locations in the cell by immunofluorescence staining and confocal microscopy. The specific goals of this proposal are to identify the mechanism for increased CXCR4 signaling in the presence of US27 and to determine whether enhanced CXCR4 responses occur in virus-infected cells. The overall goal of the project is to clarify the role of US27 in viral pathogenesi, and the results are expected to reveal a novel regulatory function for an orphan receptor with possible implications for the maintenance of HCMV latency.


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: 2019 ( Subtotal = -$1,523 )
2019	2014	UNIVERSITY OF SAN FRANCISCO INC	2130 FULTON ST	SAN FRANCISCO	CA	94117	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	6/13/2019	NEW	-$1,523
														Subtotal = -$1,523

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2014	UNIVERSITY OF SAN FRANCISCO INC	2130 FULTON ST	SAN FRANCISCO	CA	94117	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	4/6/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $424,783 )
2014	2014	UNIVERSITY OF SAN FRANCISCO	2130 FULTON ST, CAMPION C-3	SAN FRANCISCO	CA	94117	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	1	9/16/2014	NEW	$0
2014	2014	UNIVERSITY OF SAN FRANCISCO	2130 FULTON ST, CAMPION C-3	SAN FRANCISCO	CA	94117	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	3/20/2014	NEW	$424,783
														Subtotal = $424,783

Grand Total All Awards = $423,260

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Modification of Host Chemokine Responses by Human Cytomegalovirus

Award Number: R15AI111232

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: 05/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2019

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