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Influenza D Virus Entry and Tissue Tropism

Award Number: R01AI141889
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: 09/21/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Influenza D Virus Entry and Tissue Tropism - PROJECT SUMMARY Novel influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover to other mammalian hosts including pigs and horses. Of greater public health importance, serological evidence of IDV infections in humans has been demonstrated. Preliminary investigations have revealed that IDV binds to human 9-O-acetylated N-acetylneuraminic acid (Neu5,9Ac2), the receptor of human influenza C virus (ICV), and non-human N-glycolylneuraminic acid (Neu5Gc9Ac) and likely utilizes them for viral entry. Further functional studies indicate that IDV is more efficient in recognizing both human Neu5,9Ac2- and non-human Neu5Gc9Ac-containing glycans than ICV, and ICV seems to preferentially bind to human Neu5,9Ac2 over non-human Neu5Gc9Ac. In agreement with this, ICV has a limited host range with humans as a reservoir. These results suggest that IDV and ICV diverge in communicating with sialic acids (SA) for infection. The hypothesis is that subtle differences in the sequence and structure of the receptor-binding pocket residing in the hemagglutinin-esterase-fusion (HEF) protein between IDV and ICV cause substantial differences in the virus-receptor interaction, which can expand or reduce, or change tissue and species tropisms. Furthermore, the recent observation on the extracellular resistance of IDV to low pH inactivation versus the intracellular requirement of low pH for viral entry suggests a novel entry/fusion mechanism by which IDV employs to deliver its genome into the target cell. Three aims are proposed to address these hypotheses in this R01 application, which involve a comparative study of IDV and ICV. Aim 1 will elucidate the entry mechanism of IDV, while Aim 2 will define the molecular basis of the HEF receptor binding affinity and specificity and its impact on IDV tropism. Aim 3 is deigned to address how two IDV lineages, swine and bovine, read the glycan receptors differentially and how this information is transduced to different tissue and species tropisms between these two groups of IDVs. In summary, this proposal leverages the team's expertise in IDV research and novel aspects of IDV-receptor interaction and entry to elucidate the cross-species transmission mechanism of IDVs. Understanding molecular details of virus-receptor interaction may lead to development of novel strategies for the control and prevention of IDV and ICV infections in humans.


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	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	5	8/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $515,429 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	5	8/18/2022	NON-COMPETING CONTINUATION	$515,429
														Subtotal = $515,429

Issue Date FY: 2021 ( Subtotal = $518,267 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	003	4	8/20/2021	NON-COMPETING CONTINUATION	$518,267
2021	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	3	11/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2020	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	002	3	3/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$477,924
2021	2019	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	001	2	3/4/2021	NON-COMPETING CONTINUATION	-$477,924
														Subtotal = $518,267

Issue Date FY: 2020 ( Subtotal = $529,517 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	001	3	8/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$529,517
2020	2019	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	2	8/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $529,517

Issue Date FY: 2019 ( Subtotal = $524,376 )
2019	2019	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	2	8/1/2019	NON-COMPETING CONTINUATION	$524,376
														Subtotal = $524,376

Issue Date FY: 2018 ( Subtotal = $541,376 )
2018	2018	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	1	9/21/2018	NEW	$541,376
														Subtotal = $541,376

Grand Total All Awards = $2,628,965

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Influenza D Virus Entry and Tissue Tropism

Award Number: R01AI141889

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: 09/21/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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