# Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $563,732

## Abstract

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.

## Key facts

- **NIH application ID:** 10846591
- **Project number:** 5R01AI162748-04
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Muthiah Kumaraswami
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,732
- **Award type:** 5
- **Project period:** 2021-06-07 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846591

## Citation

> US National Institutes of Health, RePORTER application 10846591, Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes (5R01AI162748-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10846591. Licensed CC0.

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