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Molecular and Metabolic inter-kingdom actions of a bacterial quorum sensing signal in promotion of host tolerance/resilience.

Award Number: R01AI134857
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Our long-term goal is to develop treatments that may improve resilience to pathogen damage in patients with serious infections, including chronic and relapsing bacterial infections, for which effective treatments are lacking. Bacterial quorum sensing (QS) signals are important mediators of immunomodulation. However, it remains unclear how microbes utilize immunomodulatory signals to maintain a long-term presence and thwart clearance and how hosts avoid harmful inflammatory response to a pathogen’s presence. In our previous work, we identified a small volatile QS molecule excreted by Pseudomonas aeruginosa (PA), 2-aminoacetophenone (2-AA), that acts as an inter-kingdom “infochemical” to alter immune responses and metabolism in a manner that trains the host to increase host tolerance/resilience (HT/R), which is defined as the host's ability to cope with bacterial encounter without a consequent reduction in fitness; these alterations allow the pathogen to avoid elimination and persist in mammalian tissues. The specific goal of this application is to decipher paradigmatically the mode of action of a bacterial product on host metabolome and epigenome in order to gain insights into the first mechanistic example of a QS molecule that reprograms the host metabolome and epigenome to promote HT/R. Our hypothesis is that the long-lasting immunomodulatory changes exerted by 2-AA through the sustained activity of histone deacetylase 1 (HDAC1) derive from 2-AA–promoted metabolic alterations; and that the interplay between host metabolome and epigenome contribute to the mutual bacterial-host fitness that defines HT/R. We propose to achieve our goal through experiments employing PA, a recalcitrant Gram-negative ESKAPE bacterium that defies eradication by antibiotics, forms biofilms, and exemplifies current clinically problematic pathogens. In Aim 1, we will examine how 2-AA maintains epigenetic reprogramming by assessing the molecular mechanisms of long-term immunomodulation in immune memory in vivo promoted by 2-AA tolerization, and determine the occurring metabolic changes by performing functional studies. In Aim 2, we will interogate the capacity of 2-AA to regulate macrophage autophagy in tissues and conduct a meticulous analysis of the key host players and cellular mechanisms that permit bacterial persistence. In Aim 3, using murine in vitro and in vivo systems in addition to human primary macrophages, we will evaluate the interplay between 2-AA promoted epigenetic control and metabolic alterations by undertaking molecular and functional approaches. The impact of these alterations in bacterial persitence, histone acetylation, energy metabolism and the efficacy of our novel anti-2AA compound will be asssessed using clinically relevant animal models of infection. In Aim 4, we will seek to identify 2-AA’s direct target using click chemistry. The proposed elucidation of “host tolerance training” mechanisms is intended to improve our understanding of HT/R that remains extremely limited. In this context, the findings may offer opportunities for being applied to the development of therapeutic treatments that can train the host to augment resilience to infection. In principle, the knowledge to be obtained could be applicable to persistent infections triggered also by other bacteria because QS is broadly conserved among Gram-negative and Gram-positive human bacterial pathogens and, as such, 2-AA-like molecules are likely to exist in other bacteria.


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: 2024 ( Subtotal = $0 )
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	1/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $670,954 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	12/24/2021	NON-COMPETING CONTINUATION	$670,954
														Subtotal = $670,954

Issue Date FY: 2021 ( Subtotal = $670,954 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	1/5/2021	NON-COMPETING CONTINUATION	$670,954
														Subtotal = $670,954

Issue Date FY: 2020 ( Subtotal = $669,269 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/3/2020	NON-COMPETING CONTINUATION	$669,269
														Subtotal = $669,269

Issue Date FY: 2019 ( Subtotal = $691,129 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/11/2018	NON-COMPETING CONTINUATION	$691,129
														Subtotal = $691,129

Issue Date FY: 2018 ( Subtotal = $698,672 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	12/28/2017	NEW	$698,672
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	5/11/2018	NEW	$0
														Subtotal = $698,672

Grand Total All Awards = $3,400,978

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Molecular and Metabolic inter-kingdom actions of a bacterial quorum sensing signal in promotion of host tolerance/resilience.

Award Number: R01AI134857

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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