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Mechanisms for sensing and responding to interbacterial antagonism

Award Number: R01AI080609
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: 06/17/2009
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanisms for sensing and responding to interbacterial antagonism - Project Summary It is increasingly evident that interspecies antagonism is intrinsic to life in the bacterial kingdom. And yet, while our understanding of the antibacterial mechanisms bacteria employ in conflicts with their brethren has recently grown exponentially, our knowledge of the means by which bacteria sense and respond to antagonistic threats remains limited. In this proposal, we test the hypothesis that bacteria react to the presence of an antagonistic bacterial competitor through the activation of a multifaceted defensive program. This hypothesis grew from our discovery that Pseudomonas aeruginosa activates an extensive posttranscriptional regulatory program in response to interbacterial antagonism. The pathway, which we term PARA (Pseudomonas aeruginosa response to antagonism), is triggered when a subpopulation of P. aeruginosa cells succumb to lysis as a result of an antagonistic attack. Detection of as yet unidentified molecule(s) in cellular lysate leads to the activation of the small RNA-mediated Gac/Rsm global posttranscriptional regulatory program. Activation of this response is crucial for P. aeruginosa survival during attack, as a mutant unable to mount the response suffers a severe fitness defect during competition with antagonistic organisms. Finally, we demonstrate that the defensive response requires multiple, simultaneously acting mechanisms, including pathways of unknown function. In Aim 1 of this proposal, we will characterize one such pathway, which we name ARC1 (antagonism response complex 1). Our preliminary data indicate that ARC1 is a large membrane- associated protein complex that provides P. aeruginosa protection against antagonism mediated by toxins delivered by the type VI secretion system of a competitor species. Our studies of ARC1 will elucidate the range of threats towards which it provides protection and provide mechanistic insight into its defensive functions. In Aim 2, we will pursue complementary genetic and biochemical approaches directed at characterizing the signal present in P. aeruginosa cellular lysate responsible for triggering PARA. Finally, in Aim 3, we move beyond P. aeruginosa and ask to what extent the regulatory components behind PARA – the Gac/Rsm pathway – function generally to defend against interbacterial antagonism in other Pseudomonas species. We also examine the hypothesis that variability in the Gac/Rsm regulon reflects adaptation to the specific bacterial threats encountered by different species. Through this work, we stand to answer longstanding questions in the field, including defining the evolutionarily relevant function of an important global regulatory program and providing a molecular characterization of a long elusive signaling molecule. Additionally, through the characterization of ARC1, our work will define the mechanistic basis for participation of a conserved membrane complex of unknown function in interbacterial defense. Overall, the proposed work stands to broaden our understanding of the ways in which interbacterial antagonism shapes the course of bacterial evolution.


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 = $505,792 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	15	3/19/2025	NON-COMPETING CONTINUATION	$505,792
														Subtotal = $505,792

Issue Date FY: 2024 ( Subtotal = $505,792 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	14	3/15/2024	NON-COMPETING CONTINUATION	$505,792
														Subtotal = $505,792

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	13	5/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $524,590 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	13	3/15/2022	NON-COMPETING CONTINUATION	$524,590
														Subtotal = $524,590

Issue Date FY: 2021 ( Subtotal = $542,259 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	12	3/22/2021	NON-COMPETING CONTINUATION	$542,259
2021	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	002	11	6/3/2021	COMPETING CONTINUATION	$80,454
2021	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	10	6/3/2021	NON-COMPETING CONTINUATION	-$80,454
														Subtotal = $542,259

Issue Date FY: 2020 ( Subtotal = $504,056 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	001	11	4/15/2020	COMPETING CONTINUATION	$504,056
2020	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	10	4/7/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $504,056

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	8	3/21/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $420,970 )
2018	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	10	5/11/2018	NON-COMPETING CONTINUATION	$420,970
														Subtotal = $420,970

Issue Date FY: 2017 ( Subtotal = $420,970 )
2017	2017	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	9	5/16/2017	NON-COMPETING CONTINUATION	$420,970
														Subtotal = $420,970

Issue Date FY: 2016 ( Subtotal = $472,079 )
2016	2016	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	8	5/18/2016	NON-COMPETING CONTINUATION	$472,079
														Subtotal = $472,079

Issue Date FY: 2015 ( Subtotal = $504,637 )
2015	2015	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	7	4/27/2015	NON-COMPETING CONTINUATION	$488,116
2015	2015	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	3/26/2015	SUPPLEMENT FOR EXPANSION	$16,521
														Subtotal = $504,637

Issue Date FY: 2014 ( Subtotal = $431,794 )
2014	2014	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	5/20/2014	COMPETING CONTINUATION	$431,794
														Subtotal = $431,794

Issue Date FY: 2013 ( Subtotal = $339,615 )
2013	2013	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	5/13/2013	NON-COMPETING CONTINUATION	$339,615
														Subtotal = $339,615

Issue Date FY: 2012 ( Subtotal = $361,636 )
2012	2012	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	8/16/2012	NON-COMPETING CONTINUATION	-$82,988
2012	2012	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	4	5/8/2012	NON-COMPETING CONTINUATION	$444,624
														Subtotal = $361,636

Issue Date FY: 2011 ( Subtotal = $445,507 )
2011	2011	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	3	6/7/2011	NON-COMPETING CONTINUATION	$361,964
2011	2011	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	6/10/2011	SUPPLEMENT FOR EXPANSION	$83,543
														Subtotal = $445,507

Issue Date FY: 2010 ( Subtotal = $375,607 )
2010	2010	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Trans-NIH Recovery Act Research Support	001	2	6/7/2010	SUPPLEMENT FOR EXPANSION	$9,672
2010	2010	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	5/19/2010	NON-COMPETING CONTINUATION	$365,935
														Subtotal = $375,607

Issue Date FY: 2009 ( Subtotal = $369,935 )
2009	2009	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	1	6/12/2009	NEW	$369,935
														Subtotal = $369,935

Grand Total All Awards = $6,725,239

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Mechanisms for sensing and responding to interbacterial antagonism

Award Number: R01AI080609

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: 06/17/2009

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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