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Global regulators converge to orchestrate metabolism, biofilm, and pathogenesis

Award Number: R01AI112652
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: 08/15/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Global regulators converge to orchestrate metabolism, biofilm, and pathogenesis - Project Summary Diarrheal disease is a leading cause of morbidity and mortality in resource-poor areas. In order to colonize the intestine and cause disease, successful bacterial pathogens must sense and respond to intestinal signals by altering both metabolism and virulence factor expression. We hypothesize that by understanding the critical intestinal signals and the bacterial regulatory networks they activate, we can devise simple dietary alterations that prevent or mitigate morbidity and mortality. We focus on Vibrio cholerae, the agent of the severe diarrheal disease cholera. Because the metabolic pathways we study are highly conserved, these findings also serve as a paradigm for other bacteria that cause diarrhea. The goal of this work is to elucidate the complex and highly conserved regulatory network that is activated when V. cholerae enters the intestinal environment. In the first 4-year funding period of this grant, we explored the role of a global regulator of metabolism and virulence known as glucose-specific Enzyme llA. We showed that this regulator is membrane-associated through an N-terminal amphipathic helix and that membrane association is critical for its interaction with integral membrane protein partners that it regulates. Based on this work, we hypothesize that the inner membrane of the bacterial cell may act as a platform for regulatory proteins that sense and respond to nutritional signals in the intestinal environment. During the previous funding period, we discovered that the subcellular location of the global transcription factor, the cAMP receptor protein (CRP), is regulated in response to environmental conditions. In the current funding period, we propose to follow up on these observations by investigating regulation of CRP subcellular localization, the mechanism by which subcellular localization alters CRP activation of gene transcription, and the functional significance of CRP subcellular localization for V. cholerae virulence. We hypothesize that if the subcellular localization of CRP can be controlled via host diet, it may be possible to reduce pathogen virulence and thereby the morbidity and mortality caused by cholera.


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 = $577,362 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	2/13/2025	NON-COMPETING CONTINUATION	$577,362
														Subtotal = $577,362

Issue Date FY: 2024 ( Subtotal = $573,979 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	8	5/20/2024	NON-COMPETING CONTINUATION	$57,397
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	2/7/2024	NON-COMPETING CONTINUATION	$516,582
														Subtotal = $573,979

Issue Date FY: 2023 ( Subtotal = $582,121 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	3/2/2023	NON-COMPETING CONTINUATION	$582,121
														Subtotal = $582,121

Issue Date FY: 2022 ( Subtotal = $591,679 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	3/18/2022	NON-COMPETING CONTINUATION	$591,679
														Subtotal = $591,679

Issue Date FY: 2021 ( Subtotal = $721,490 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	5	3/31/2021	COMPETING CONTINUATION	$332,434
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	5	9/27/2021	COMPETING CONTINUATION	$389,056
2021	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	2/6/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $721,490

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	8/2/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $557,550 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	7/25/2017	NON-COMPETING CONTINUATION	$557,550
														Subtotal = $557,550

Issue Date FY: 2016 ( Subtotal = $557,550 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	7/14/2016	NON-COMPETING CONTINUATION	$557,550
														Subtotal = $557,550

Issue Date FY: 2015 ( Subtotal = $513,904 )
2015	2015	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	7/15/2015	NON-COMPETING CONTINUATION	$513,904
														Subtotal = $513,904

Issue Date FY: 2014 ( Subtotal = $470,690 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/8/2014	NEW	$470,690
														Subtotal = $470,690

Grand Total All Awards = $5,146,325

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Global regulators converge to orchestrate metabolism, biofilm, and pathogenesis

Award Number: R01AI112652

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: 08/15/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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