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Molecular determinants of Salmonella cell-envelope copper homeostasis

Award Number: R01AI150784
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: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Molecular determinants of Salmonella cell-envelope copper homeostasis - Project Summary The goal of this proposal is to define the mechanisms of Cu homeostasis in the cell envelope of the pathogen Salmonella enterica. This organism is an important and frequent cause of gastroenteritis, as well as, systemic infections. Cu is required as a redox co-factor in the catalytic centers of enzymes. However, free Cu is highly reactive and deleterious to cells. Cu, along with the oxidative burst, is central in host-pathogen interactions as part of the innate immune response. As such, redox/Cu homeostasis is essential for bacterial virulence. While there has been significant progress in identifying cytoplasmic Cu homeostatic mechanisms, there is a lack of understanding of how the cell envelope handles and distributes Cu, whilst maintaining the associated redox balance. Our goal is to define and model the Cu distribution in the Salmonella cell envelope and identify its molecular links with the redox stress response. The aims of this proposal are: 1) Quantify Cu fluxes and equilibria among periplasmic, cytoplasmic and external compartments while defining the size and identity of the periplasmic Cu sink pool. 2) Define the role of CueP as the periplasmic Cu chaperone exchanging the metal with various targets. We will monitor CueP in vivo abundance, as well as its apo/holo equilibria, in response to changes in periplasmic Cu levels. We will determine how CueP obtains Cu from membrane transporters in the inner and outer membranes and delivers it to alternative carriers to achieve steady state levels of periplasmic Cu. CueP participation in the metallation of several periplasmic cuproenzymes will be assessed. 3) Determine the role of the ScsABCD system at the interface of Cu- and redox-homeostasis. The redox activity of these enzymes will be determined and in vivo substrates identified. The relation between ScsABCD activity and Cu binding to substrates or among ScsABCD enzymes will be established. To achieve these aims, the joint efforts of two laboratories with complementing expertise will use a combination of approaches (modeling of metal fluxes, proteomics, metallomics, in vitro host/pathogen interaction). Our approach to systematically elucidate the mechanisms of Cu/redox homeostasis in the envelope of an important human pathogen is novel, timely and innovative.


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: 2026 ( Subtotal = -$68,060 )
2026	2024	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	1/29/2026	NON-COMPETING CONTINUATION	-$68,060
														Subtotal = -$68,060

Issue Date FY: 2024 ( Subtotal = $433,610 )
2024	2024	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	7/8/2024	NON-COMPETING CONTINUATION	$433,610
														Subtotal = $433,610

Issue Date FY: 2023 ( Subtotal = $433,610 )
2023	2023	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	7/20/2023	NON-COMPETING CONTINUATION	$433,610
														Subtotal = $433,610

Issue Date FY: 2022 ( Subtotal = $433,610 )
2022	2022	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	7/19/2022	NON-COMPETING CONTINUATION	$433,610
														Subtotal = $433,610

Issue Date FY: 2021 ( Subtotal = $447,052 )
2021	2021	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	7/28/2021	NEW	$447,052
														Subtotal = $447,052

Grand Total All Awards = $1,679,822

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Molecular determinants of Salmonella cell-envelope copper homeostasis

Award Number: R01AI150784

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: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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