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Molecular Basis for the Reciprocal Regulation of P. aeruginosa Virulence Factors by the Signaling Kinase RetS

Award Number: R21AI128255
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:

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Molecular Basis for the Reciprocal Regulation of P. aeruginosa Virulence Factors by the Signaling Kinase RetS Abstract The nosocomial pathogen Pseudomonas aeruginosa causes acute and persistent, chronic infections using distinct virulence mechanisms. The sensor signaling kinase RetS is a major player in regulating these virulence mechanisms by inhibiting the signaling kinase GacS. The unique molecular mechanism underlying this inhibition has not been determined. Our preliminary data refute the original hypothesis that RetS interferes with GacS homo-dimerization. Here we propose to test an alternative model wherein RetS directly blocks the active and phosphorylation sites of GacS. The second part of the proposed work seeks to determine how this inhibition is relieved when the bacterium enters biofilm mode to cause an expression of entirely different set of virulence factors. We hypothesize that binding of the exopolysaccharide PSL to the sensory domain of RetS causes RetS autophosphorylation, which in turn triggers the release of GacS. Structural studies and a series of in vitro and in vivo assays are proposed to address these important biological questions. In addition, the use of the NarX sensory domain to regulate the kinase activity of RetS constitutes an important extension of previous applications. We are controlling an enzyme that does not have a HAMP domain normally required for NarX signaling. If our approach is successful it could be applied to studies of many more orphan signaling kinases.


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 = -$6,935 )
2022	2018	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	11/17/2021	NON-COMPETING CONTINUATION	-$6,935
														Subtotal = -$6,935

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	5/19/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $192,762 )
2018	2018	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	3/23/2018	NON-COMPETING CONTINUATION	$192,762
														Subtotal = $192,762

Issue Date FY: 2017 ( Subtotal = $225,333 )
2017	2017	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW, SUITE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	5/18/2017	NEW	$225,333
														Subtotal = $225,333

Grand Total All Awards = $411,160

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Molecular Basis for the Reciprocal Regulation of P. aeruginosa Virulence Factors by the Signaling Kinase RetS

Award Number: R21AI128255

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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