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Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

Award Number: R01AI162748
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: 06/07/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes - Pathogenic bacteria survive in complex and hostile environments in the host. Several host- and microbiota-derived factors curb pathogen growth during infection. Successful pathogens respond by exploiting the cues in their immediate environment to coordinate spatiotemporal production of virulence factors. Our preliminary data indicate that the human pathogen group A streptococcus (GAS) is engaged in arms race with a commensal bacterium during oropharyngeal infection. The commensal bacteria produce a previously unknown antimicrobial metabolite with a novel chemical scaffold that may contribute to host defense against GAS colonization in human oropharynx. As a countermeasure, GAS employs secreted cysteine protease SpeB, a major virulence factor, to overcome commensal defenses by proteolytically degrading the antimicrobial metabolites. Despite our experimental evidence suggesting antagonism between GAS and commensal bacterium, the factors and mechanisms that regulate antimicrobial metabolite production in the commensal and their influence on SpeB production by GAS are unknown. Recently, we discovered a novel GAS quorum sensing pathway comprised of a new class of bacterial quorum sensing signal, a leaderless secreted peptide, and an intracellular receptor that controls the temporal expression of speB during infection. Interestingly, the commensal bacterium also employs a leaderless peptide-dependent quorum sensing pathway to control the antimicrobial metabolite production. However, our preliminary data suggest that GAS hijacks the commensal peptide signal to induce its endogenous quorum sensing pathway and activate SpeB production. This finding is highly relevant to GAS pathogenesis as the interspecies signaling facilitates virulence factor production in a suboptimal host environment and promotes GAS virulence. Using a multidisciplinary approach combining microbiological, genetic, biochemical and imaging methodologies, and animal infection studies, we will dissect the molecular details of intra- and inter- species signaling, characterize the mechanism of antagonism between the two bacterial species, determine its impact on GAS pathogenesis, and elucidate the mechanism of intercellular signaling by leaderless peptides in four specific aims. The results from this study will elucidate how the peptide signaling pathways are tailored for the physiological needs of the producing bacteria and how a pathogen gain survival advantage by hijacking the non-cognate signal from a commensal microbe to trigger virulence factor production and cause disease. The proposed research is significant as it investigates a critical process in disease pathogenesis of a major human pathogen and is likely to elucidate novel translational strategies to combat GAS infections.


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 = $0 )
2026	2025	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	4/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $563,732 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	8/7/2025	NON-COMPETING CONTINUATION	$563,732
														Subtotal = $563,732

Issue Date FY: 2024 ( Subtotal = $563,732 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	5/24/2024	NON-COMPETING CONTINUATION	$563,732
														Subtotal = $563,732

Issue Date FY: 2023 ( Subtotal = $563,732 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	3	5/23/2023	NON-COMPETING CONTINUATION	$563,732
														Subtotal = $563,732

Issue Date FY: 2022 ( Subtotal = $563,732 )
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	5/6/2022	NON-COMPETING CONTINUATION	$563,732
														Subtotal = $563,732

Issue Date FY: 2021 ( Subtotal = $563,732 )
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	6/4/2021	NEW	$563,732
														Subtotal = $563,732

Grand Total All Awards = $2,818,660

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Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

Award Number: R01AI162748

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: 06/07/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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