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Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infection

Award Number: R01AI083387
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Innate immunity constitutes pro-inflammatory response to initiate inflammation for adaptive immune response required for virus clearance. Pro-inflammatory (and inflammation) response need to be “tightly” regulated during virus infection since exaggerated inflammation contributes to inflammatory diseases. Activation of Pattern Recognition Receptors (PRRs) is critical for triggering innate immunity and inflammation during infection with human respiratory syncytial virus (RSV) and influenza A virus (IAV). Therefore, it is important to study the underlying cellular/molecular mechanism involved in transducing optimal innate immunity and inflammatory (and pro-inflammatory) response upon PRR activation. We have surprisingly identified a novel signaling network that is required for optimal pro-inflammatory response following PRR activation. Our preliminary result suggested that an oxysterol (a bioactive lipid) 25-hydroxycholesterol (25HC) play an important role in magnifying and intensifying pro-inflammatory response following activation of PRRs and during virus (RSV, IAV) infection. Surprisingly we observed interaction of 25HC with cell surface integrins and further preliminary studies suggested a possible mechanism. Mechanistically, we postulate that 25HC released from PRR activated (and virus infected) cells act as an extracellular soluble mediator to activate 25HC--- integrin (¿5¿1, ¿V¿3 integrins)---FAK (focal adhesion kinase)---NF¿B pathway for optimal pro-inflammatory response. Thus, we envision that extracellular 25HC serve as a “linker” (via autocrine/paracine mechanism) to bridge PRR pathway with integrin pathway for optimal pro-inflammatory response. We hypothesize that - a) extracellular 25HC links PRR pathway with integrin pathway; b) PRR---25HC---integrin---FAK---NF¿B signaling network magnifies pro-inflammatory response and inflammation; and c) 25HC--- integrin---FAK signaling pathway contributes to exaggerated inflammation during RSV and IAV infection, thus leading to development of exacerbated airway diseases like pneumonia and bronchiolitis. In the current proposal we have selected a membrane bound PRR (i.e. toll-like receptor 3 or TLR3) and a cytosolic PRR (i.e. Nod2) along with two clinically important respiratory viruses (RSV, IAV) to elucidate the role of 25HC---integrin---FAK---NF¿B pathway in promoting optimal and maximal pro-inflammatory response. In aim-1 we will investigate interaction of 25HC with integrins leading to activation of integrin---FAK---NF¿B pathway and subsequent pro- inflammatory response in macrophages. In aim-2 we will examine the role of 25HC---integrin---FAK---NF¿B pathway in triggering optimal pro-inflammatory response in macrophages following PRR (TLR3, Nod2) activation and virus (RSV, IAV) infection. Finally, in aim-3 we will utilize knockout mice to study physiological in vivo role of 25HC---integrin---FAK pathway during PRR (Nod2, TLR3) activation and virus (RSV, IAV) infection. Significance –Our current proposal has wide implication in development of therapeutics against RSV, IAV and other pathogens that activate PRRs.


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: 2023 ( Subtotal = $0 )
2023	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	10	6/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $375,233 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	10	7/13/2021	NON-COMPETING CONTINUATION	$375,233
														Subtotal = $375,233

Issue Date FY: 2020 ( Subtotal = $375,233 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	9	6/12/2020	NON-COMPETING CONTINUATION	$375,233
														Subtotal = $375,233

Issue Date FY: 2019 ( Subtotal = $375,233 )
2019	2019	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	8	8/1/2019	NON-COMPETING CONTINUATION	$375,233
														Subtotal = $375,233

Issue Date FY: 2018 ( Subtotal = $375,233 )
2018	2018	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	7	8/8/2018	COMPETING CONTINUATION	$375,233
														Subtotal = $375,233

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	6	9/26/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	WASHINGTON STATE UNIVERSITY	FRENCH ADMIN BLDG, ROOM 240K	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	6	5/12/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $336,353 )
2014	2014	WASHINGTON STATE UNIVERSITY	FRENCH ADMIN BLDG, ROOM 240K	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	002	6	5/15/2014	NON-COMPETING CONTINUATION	$336,353
2014	2013	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	3/28/2014	NON-COMPETING CONTINUATION	-$67,132
2014	2013	WASHINGTON STATE UNIVERSITY	FRENCH ADMIN BLDG, ROOM 240K	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	001	5	4/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$67,132
														Subtotal = $336,353

Issue Date FY: 2013 ( Subtotal = $310,937 )
2013	2013	WASHINGTON STATE UNIVERSITY	FRENCH ADMIN BLDG, ROOM 240K	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	002	5	4/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$67,132
2013	2013	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	4	3/28/2014	NON-COMPETING CONTINUATION	-$67,132
2013	2013	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	5/15/2013	NON-COMPETING CONTINUATION	$310,937
														Subtotal = $310,937

Issue Date FY: 2012 ( Subtotal = $330,784 )
2012	2012	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	5/23/2012	NON-COMPETING CONTINUATION	$330,784
2012	2012	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	8/24/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $330,784

Issue Date FY: 2011 ( Subtotal = $330,784 )
2011	2011	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	6/10/2011	NON-COMPETING CONTINUATION	$330,784
														Subtotal = $330,784

Issue Date FY: 2010 ( Subtotal = $334,125 )
2010	2010	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	5/24/2010	NEW	$334,125
														Subtotal = $334,125

Grand Total All Awards = $3,143,915

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Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infection

Award Number: R01AI083387

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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