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Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

Award Number: R01HL107380
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia - SUMMARY Pneumonia, caused by bacterial and/or viral etiology, is the leading cause of death in children worldwide. Preceding viral illness, linked to influenza infection, is a primary risk factor associated with secondary bacterial pneumonia. Influenza infection is an annual, seasonal cause of morbidity and mortality throughout the world. Severe influenza pneumonia is often exacerbated by bacterial infection resulting in poor patient outcomes even in previously healthy individuals. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence and is now more common than Streptococcus pneumoniae, the previously predominant pathogen. The lack of effective anti-viral therapeutics, immunomodulatory drugs, and increasing antibiotic resistance, coupled with poor vaccine coverage and efficacy, results in a dire need for novel therapeutic target identification. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during seasonal and pandemic outbreaks. During the previous funding periods, our laboratory has identified suppression of bacterial-induced Type 17 immune responses by preceding influenza as a critical susceptibility mechanism. We have published extensively in this area, elucidating aberrant host defense pathways in this context. In this application, we will build upon our ongoing work with two highly novel Aims derived from the original focus. We now provide preliminary data implicating a detrimental role for type III interferon (IFNλ) in super-infection through inhibiting monocyte function and pattern recognition receptor expression. These data support the hypothesis that influenza induced IFNλ directly inhibits monocyte antibacterial function via suppression of SIGNR3/4, which is required for subsequent activation of Type 17 immunity and S. aureus clearance during super-infection. In Aim 1, we will determine the mechanism by which IFNλ inhibits monocyte function during influenza, S. aureus super-infection. In Aim 2, we will define the role of SIGNR3/4 in host defense against S. aureus in the lung. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1) and how the immune response to influenza attenuate S. aureus clearance in the lung (Aim 2). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super-infection and identify novel treatment targets in a pre-clinical model of disease.


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 = $496,186 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	13	6/20/2024	NON-COMPETING CONTINUATION	$40,505
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	13	3/25/2024	NON-COMPETING CONTINUATION	$455,681
														Subtotal = $496,186

Issue Date FY: 2023 ( Subtotal = $506,312 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	12	6/9/2023	NON-COMPETING CONTINUATION	$506,312
														Subtotal = $506,312

Issue Date FY: 2022 ( Subtotal = $540,727 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	003	11	6/15/2022	NON-COMPETING CONTINUATION	$54,074
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	002	11	4/6/2022	NON-COMPETING CONTINUATION	$486,653
2022	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	10	11/1/2021	COMPETING CONTINUATION	$1,903
2022	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	9	11/1/2021	NON-COMPETING CONTINUATION	-$1,903
														Subtotal = $540,727

Issue Date FY: 2021 ( Subtotal = $506,378 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	002	10	8/4/2021	COMPETING CONTINUATION	$50,637
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	10	4/8/2021	COMPETING CONTINUATION	$455,741
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	9	7/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $506,378

Issue Date FY: 2020 ( Subtotal = $391,250 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	9	3/24/2020	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2019 ( Subtotal = $391,250 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	8	3/13/2019	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2018 ( Subtotal = $390,626 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	7	3/23/2018	NON-COMPETING CONTINUATION	$382,813
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	7	6/16/2018	NON-COMPETING CONTINUATION	$7,813
														Subtotal = $390,626

Issue Date FY: 2017 ( Subtotal = $387,813 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	6	3/31/2017	COMPETING CONTINUATION	$387,813
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	003	6	5/26/2017	COMPETING CONTINUATION	$259
2017	2016	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	5	4/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2016	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	002	5	5/26/2017	EXTENSION WITH OR WITHOUT FUNDS	-$259
														Subtotal = $387,813

Issue Date FY: 2016 ( Subtotal = $372,570 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	5	1/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$5,589
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	5	12/8/2015	EXTENSION WITH OR WITHOUT FUNDS	$366,981
														Subtotal = $372,570

Issue Date FY: 2015 ( Subtotal = $366,981 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	4	2/24/2015	NON-COMPETING CONTINUATION	$31,668
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	4	12/15/2014	NON-COMPETING CONTINUATION	$335,313
														Subtotal = $366,981

Issue Date FY: 2014 ( Subtotal = $365,119 )
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	3	2/27/2014	NON-COMPETING CONTINUATION	$29,806
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	3	12/13/2013	NON-COMPETING CONTINUATION	$335,313
														Subtotal = $365,119

Issue Date FY: 2013 ( Subtotal = $354,687 )
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	001	2	6/25/2013	NON-COMPETING CONTINUATION	$19,374
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	2	12/13/2012	NON-COMPETING CONTINUATION	$335,313
														Subtotal = $354,687

Issue Date FY: 2012 ( Subtotal = $372,570 )
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	1	12/9/2011	NEW	$372,570
														Subtotal = $372,570

Grand Total All Awards = $5,442,469

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Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

Award Number: R01HL107380

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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