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Second Messenger Nucleotides of Enterococcus faecalis

Award Number: R01AI172179
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: 03/17/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Second Messenger Nucleotides of Enterococcus faecalis - ABSTRACT Enterococci are the 3rd most common cause of hospital-acquired infections and a major public health threat due to the continuous rise of multidrug-resistant (MDR) isolates. Because the pathogenic potential of enterococci is closely linked to their ubiquitous stress resilience, work in our lab aims to identify and dissect the mechanisms that allow Enterococcus faecalis, the most prevalent enterococcal species of human infections, to survive in the hostile host environment. Second messenger nucleotides such as (p)ppGpp (the effector molecule of the stringent response) and c-di-AMP are produced by bacteria in response to internal or external stimuli, playing major roles in the regulation of processes associated with cell homeostasis and virulence. In addition, cyclic nucleotides such as c-di-AMP act as agonists of the innate immune response of mammalians by stimulating a potent STING-dependent type I interferon response. Of interest, previous investigations have shown that the c-di-AMP and (p)ppGpp signaling networks are interconnected in other bacteria, but a clear understanding of the mechanics and physiological significance of this interaction are still lacking. In previous studies, we discovered that E. faecalis depends on small amounts of (p)ppGpp to maintain a balanced metabolism and to respond to external cues in an accurate and timely manner. We also found that lack of (p)ppGpp greatly increases antibiotic sensitivity and attenuates the virulence of E. faecalis. More recently, we showed that c-di-AMP is also critical to E. faecalis pathophysiology and that either accumulation or lack of c- di-AMP can drastically impair the virulence potential of E. faecalis. The goals of this application are: (i) to probe the multifaceted roles played by c-di-AMP during infection using a catheter-associated urinary tract infection (CAUTI) mouse model that recapitulates many of the clinical characteristics of the disease in humans, (ii) to identify and characterize the c-di-AMP binding/effector proteins in E. faecalis, and (iii) to investigate how integration of the c-di-AMP and (p)ppGpp regulatory networks controls specific processes that promote bacterial fitness and then determine how this association contributes to E. faecalis pathophysiology. This conceptually innovative application builds on our extensive preliminary data and the complementary expertise and solid track record of our research team in each specific area of this application. Significance of the proposed studies lies in unravelling the multifaceted role of c-di-AMP in host-pathogen interactions, uncovering the scope of c-di-AMP regulation in a major MDR pathogen, and shedding new light onto the intricate relationship between c-di-AMP and (p)ppGpp. Given the central role of regulatory nucleotides in bacterial pathogenesis, a better understanding of how they modulate cell physiology based on identification and characterization of their mechanisms of action and effectors can facilitate the rational design of new antimicrobial therapies.


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 = $492,854 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	4	2/9/2026	NON-COMPETING CONTINUATION	$492,854
														Subtotal = $492,854

Issue Date FY: 2025 ( Subtotal = $500,046 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$500,046
														Subtotal = $500,046

Issue Date FY: 2024 ( Subtotal = $860,482 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	2	2/8/2024	NON-COMPETING CONTINUATION	$504,405
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	2	5/23/2024	NON-COMPETING CONTINUATION	$56,045
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	1/2/2024	NEW	$300,032
														Subtotal = $860,482

Issue Date FY: 2023 ( Subtotal = $289,869 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	3/16/2023	NEW	$289,869
														Subtotal = $289,869

Grand Total All Awards = $2,143,251

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Second Messenger Nucleotides of Enterococcus faecalis

Award Number: R01AI172179

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: 03/17/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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