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Endothelial cell tropism in the pathogenesis and host response against influenza viruses - Resubmission 01

Award Number: R01AI127775
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: 12/08/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Endothelial cell tropism in the pathogenesis and host response against influenza viruses - Resubmission 01 - ABSTRACT Influenza A viruses pose a serious threat to human health, causing seasonal epidemics and occasional pandemics that result in significant morbidity and mortality worldwide. The virulence and pathogenic nature of influenza virus strains vary greatly, and is often determined by the constellation of viral genes. While seasonal influenza viruses cause a mild upper respiratory infection in healthy individuals, highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype replicate in the lower respiratory tract, causing fatal viral pneumonia characterized by pulmonary edema and vascular leakage. In addition, H5N1 infections are associated with an uncontrolled activation of host immune responses, which contributes to the severity of disease. The role of viral and host factors in the enhanced virulence and pulmonary immunopathology characteristic of HPAIV infections remain unknown. To this end, we engineered H5N1 viruses with restricted tropism through the incorporation of microRNA (miRNA) target sites into the viral genome. Specifically, we generated an H5N1 virus carrying endothelial cell specific miR-126 target sites (H5N1-126T), such that viral replication was abrogated in endothelial cells without impeding replication in other cell types. In our recent studies, H5N1-126T infected mice and ferrets showed significantly reduced virulence and vascular leakage in the lungs as compared to the control H5N1-ScrbT virus infected group, despite similar viral loads in the lungs of mice and nasal washes of ferrets. To our knowledge, this is the first study to demonstrate the importance of endothelial cell tropism to H5N1 pathogenesis. The current proposal will (1) determine the consequence of endothelial cell infection to barrier integrity and function, (2) investigate the role of endothelial cell tropism in orchestrating immune responses, and (3) assess the contribution of viral tropism to the pathogenesis of other highly virulent strains including H7N7, 1918 H1N1, and H7N9 in mice and ferrets. The knowledge gained from these studies will help to elucidate the mechanism by which virulent influenza viruses cause severe disease and aid in the development of novel therapeutic strategies against virulent influenza strains. Furthermore, these studies will reveal how viral tropism modulates host antiviral responses and will pave the way for the rational design of novel live attenuated vaccines with restricted tropism.


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: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	6	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $540,271 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	6	9/20/2022	NON-COMPETING CONTINUATION	$540,271
														Subtotal = $540,271

Issue Date FY: 2021 ( Subtotal = $540,271 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	5	11/16/2020	NON-COMPETING CONTINUATION	$540,271
														Subtotal = $540,271

Issue Date FY: 2020 ( Subtotal = $539,422 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	4	1/16/2020	NON-COMPETING CONTINUATION	$539,422
														Subtotal = $539,422

Issue Date FY: 2019 ( Subtotal = $556,280 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	004	3	5/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,803
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	2	2/28/2019	NON-COMPETING CONTINUATION	-$560,456
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	11/21/2018	NON-COMPETING CONTINUATION	$560,456
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	001	3	2/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$556,280
2019	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	003	1	5/8/2019	NEW	-$333,803
														Subtotal = $556,280

Issue Date FY: 2018 ( Subtotal = $580,820 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	12/8/2017	NEW	$580,820
														Subtotal = $580,820

Grand Total All Awards = $2,757,064

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Endothelial cell tropism in the pathogenesis and host response against influenza viruses - Resubmission 01

Award Number: R01AI127775

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: 12/08/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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