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The role of Bik in the replication and severity of influenza A virus

Award Number: R01AI148180
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: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The role of Bik in the replication and severity of influenza A virus - Influenza A virus (IAV) is responsible for seasonal epidemics that results in severe respiratory illness and deaths worldwide, costing billions of dollars annually in the U.S. alone. Cancer patients are at increased risk of developing a secondary pneumonia after influenza, which can lead to significant complications. Influenza infections pose serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus, and rapid development of drug resistance. New approaches to control infection may stem from cellular factors or pathways that directly or indirectly interact with viral proteins to enhance or inhibit virus replication. One of the emerging concepts in the field of IAV is that host cellular factors and pathways are required for maintaining IAV genome integrity, which is essential for viral replication. Our preliminary data show that a deficiency of a host cellular protein, Bik, is associated with significant reduction in IAV replication. Our major findings found that Bik deficiency reduces viral protein levels and viral replication in infected airway epithelial cells. Furthermore, bik-/- compared to bik+/+ mice exhibit less severe lung inflammation, reduced lung viral load, and a significant increase in survival rate after infection with IAV. Similarly, a single nucleotide polymorphism (SNP) in the BIK gene (G→A) that increases Bik expression levels significantly increases viral NP level and replication in primary normal human bronchial epithelial cells (NHBEs). Furthermore, data from an IAV- infected human cohort showed that the AA variant of BIK SNP is a risk allele associated with influenza disease severity. Bik disrupts the interaction of Bcl-2 with IAV-encoded nucleoprotein (NP) and form a Bik/NP complex that may help assemble viral proteins. The goals of this proposal are to define the role of a host cell protein Bik in promoting viral replication. Our central hypothesis is that IAV increases host cell Bik protein expression, which interacts with and disrupts Bcl-2/NP interaction to allow NP to assemble components of viral ribonucleoprotein (vRNP) and facilitate efficient viral replication. To test this hypothesis, we propose two Specific Aims. Aim 1 identifies the Bik-binding domain of viral NP required for IAV replication. Aim 2 determines whether a BIK SNP associated with increased Bik expression is a risk factor for influenza disease severity in humans. Studies are designed to identify the sites of Bik/NP interaction that may serve as potential drug targets in the future. This study may identify underlying host genetic risk factors contributing to influenza susceptibility and severity and may have potential implications in regard to targeted prevention and treatment based on susceptibility factors. The proposed studies will have significant impacts on the field by dissecting key mechanisms that promote IAV replication. In the long term, developing peptides or small molecules that disrupt Bik/NP interactions may improve therapy by reducing IAV replication. Further, this study will identify genetic factors contributing to IAV disease severity, which can have a broad public health significance.


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: 2025 ( Subtotal = $396,208 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	6	12/19/2024	NON-COMPETING CONTINUATION	$396,208
														Subtotal = $396,208

Issue Date FY: 2024 ( Subtotal = $396,208 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	004	5	5/21/2024	NON-COMPETING CONTINUATION	$39,622
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	12/12/2023	NON-COMPETING CONTINUATION	$356,586
2024	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	2	2/6/2024	NON-COMPETING CONTINUATION	-$291,933
2024	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	003	3	2/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$347,757
2024	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	2/6/2024	NEW	-$55,824
														Subtotal = $396,208

Issue Date FY: 2023 ( Subtotal = $402,475 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	4	12/19/2022	NON-COMPETING CONTINUATION	$402,475
2023	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	3	11/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$151,013
2023	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	11/16/2022	NON-COMPETING CONTINUATION	-$151,013
														Subtotal = $402,475

Issue Date FY: 2022 ( Subtotal = $442,946 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/22/2021	NON-COMPETING CONTINUATION	$442,946
														Subtotal = $442,946

Issue Date FY: 2021 ( Subtotal = $462,696 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	12/29/2020	NEW	$462,696
														Subtotal = $462,696

Grand Total All Awards = $2,100,533

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The role of Bik in the replication and severity of influenza A virus

Award Number: R01AI148180

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: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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