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Control of virulence in Vibrio cholerae by fatty acids

Award Number: R01AI120068
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: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Control of virulence in Vibrio cholerae by fatty acids - Vibrio cholerae O1 causes the fatal epidemic disease cholera. The ability of V. cholerae to cause disease in humans is dependent upon two primary virulence factors, the toxin-coregulated pilus (TCP), a critical colonization factor, and cholera toxin (CT). The expression of these factors is controlled by a highly regulated transcriptional cascade that serves as a paradigm for the regulation of bacterial virulence. Expression of the cascade is initiated at the tcpPH promoter by a cooperative interaction between the regulators AphA and AphB. TcpPH and ToxRS are homologous pairs of transmembrane regulators that then cooperate to activate expression from the toxT promoter. ToxT, an AraC-type regulator, directly activates the expression of TCP and CT. Transcriptional activation of the virulence cascade is strongly dependent upon a variety of stimuli from the external environment. The long-term goals of this proposal are to understand the molecular basis of virulence gene regulation in V. cholerae so as to facilitate the development of new strategies to control its infectivity. Through a collaborative effort involving laboratories with expertise in structural biology, virulence gene regulation and pathogenesis, we have found that exogenous unsaturated fatty acids (UFAs), which are components of human bile, are capable of binding to ToxT and impairing its ability to activate virulence gene expression. UFAs bind into a ligand pocket in the N-terminal domain of ToxT and inhibit its dimerization as well as its ability to bind to DNA. Bicarbonate, which neutralizes the acid that comes from the stomach, has been shown to function as a second in vivo signal that, in contrast to UFAs, stimulates ToxT and enhances its DNA binding through an unknown mechanism. We have recently identified a new link between fatty acids (FAs) and virulence gene expression in the current pandemic strain of V. cholerae with the discovery that the master regulator of FA metabolism, FadR, influences the translation of ToxT by an unknown mechanism. This proposal will build upon the ToxT structural and functional data, as well as our recent studies involving FadR, in order to elucidate several key mechanisms involved in regulating the expression of the virulence cascade. In Aim 1, we propose to elucidate the allosteric mechanisms controlling the dimerization of ToxT and to investigate the opposing effects of UFAs and bicarbonate on this process. In Aim 2, we propose to elucidate the mechanism by which FadR influences the translation of ToxT in V. cholerae. These studies will contribute significantly toward our understanding of how virulence gene expression is regulated in V. cholerae and will likely provide new avenues for antivirulence drug discovery.


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: 2022 ( Subtotal = $0 )
2022	2020	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	11/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $429,788 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	6/24/2020	NON-COMPETING CONTINUATION	$405,000
2020	2016	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	1	9/15/2020	NEW	$24,788
														Subtotal = $429,788

Issue Date FY: 2019 ( Subtotal = $405,000 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	7/2/2019	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2018 ( Subtotal = $405,000 )
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	5/30/2018	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2017 ( Subtotal = $405,000 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	6/26/2017	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2016 ( Subtotal = $371,251 )
2016	2016	DARTMOUTH COLLEGE	11 ROPE FERRY ROAD, #6210	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	6/29/2016	NEW	$371,251
														Subtotal = $371,251

Grand Total All Awards = $2,016,039

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Control of virulence in Vibrio cholerae by fatty acids

Award Number: R01AI120068

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: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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