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Mechanism and Functional Impact of H5N1 Influenza Virus Replication in Macrophages

Award Number: R15AI111307
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: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2019

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Mechanism and Functional Impact of H5N1 Influenza Virus Replication in Macrophages - DESCRIPTION (provided by applicant): Highly pathogenic avian (HPAI) H5N1 influenza viruses are associated with a 50% mortality rate in humans and are considered a primary pandemic threat. Although the mechanism by which these viruses cause severe disease is not fully defined, an overly aggressive immune response is a hallmark of H5N1 disease. Macrophages, though critical for protection against influenza virus infection, have been implicated in severe H5N1 disease primarily through the production of excessive levels of pro-inflammatory cytokines. The preliminary evidence for this proposed project demonstrates that a defining feature of HPAI H5N1 influenza viruses is their ability to productively replicate in macrophages in a hemagglutinin (HA)-dependent manner while non-H5 influenza viruses are degraded in the cytoplasm upon viral entry. Further, the ability of H5N1 viruses to replicate in macrophages is associated with disease severity in vivo. It is unclear how H5N1 influenza viruses subvert cellular pathways which restrict influenza virus replication in macrophages. This proposal tests the hypothesis that the cellular pathway of autophagy restricts non-H5 influenza virus replication in macrophages by targeting them for degradation in the lysosome while H5N1 viruses fail to activate autophagy, thus being enabled to complete the viral replication cycle. Further, we hypothesize that H5N1 influenza virus replication in macrophages alters cellular functions. The hypothesis will be tested using a parental H1 influenza virus and a reverse genetics-derived virus expressing an H5 HA protein that has been deselected to permit its safe use under BSL2 laboratory conditions. Specific Aim 1 tests the model that autophagy restricts non-H5 influenza virus replication. A combination of confocal imaging and western blots will be used to detect autophagy activation during virus infection. Infections will be carried out in the presence of autophagy inhibitors and virus replication will be determined by quantitative real-time PCR. Specific Aim 2 tests the hypothesis that macrophage function is impaired by replication of H5N1 viruses. Proinflammatory cytokine and nitric oxide levels will be determined by enzyme-linked immunosorbent assay (ELISA) and a phagocytosis assay will be used to determine changes in macrophage function in cells infected with viruses that do or do not replicate in that cell type. The data generated by this proposal will not only increase our understanding of how H5N1 influenza viruses cause excessive disease, but will also increase our understanding of how microbes "hijack" antiviral pathways in macrophages to support their own replication. Thus, the proposed project will potentially have an important impact on the broader field of pathogens that infect macrophages.


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: 2020 ( Subtotal = -$14,288 )
2020	2015	CHICO STATE ENTERPRISES	25 MAIN ST UNIT 203	CHICO	CA	95928	BUTTE	USA	Allergy and Infectious Diseases Research	000	1	2/27/2020	NEW	-$14,288
														Subtotal = -$14,288

Issue Date FY: 2015 ( Subtotal = $334,656 )
2015	2015	CSU, CHICO RESEARCH FOUNDATION	CHICO BMU 219	CHICO	CA	95929	BUTTE	USA	Allergy and Infectious Diseases Research	000	1	8/25/2015	NEW	$334,656
														Subtotal = $334,656

Grand Total All Awards = $320,368

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Mechanism and Functional Impact of H5N1 Influenza Virus Replication in Macrophages

Award Number: R15AI111307

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: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2019

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