# Novel Therapeutic Approach to Invasive Group A Streptococcal Disease

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $236,250

## Abstract

ABSTRACT
Microbial-derived Short Chain Fatty Acids (SCFAs) have emerged as important mediators of
“Disease Tolerance,” a process that seeks to limit collateral damage to host tissues that
accompanies immune responses. SCFAs are the principle end-products of the metabolism of the
Gram-positive pathogen Streptococcus pyogenes which can cause several severe invasive
diseases that are notoriously difficult to treat due to extensive and rapid tissue destruction that
limits perfusion of antibiotics to the site of bacterial multiplication. For the most severe
manifestations, in particular necrotizing fasciitis, lesions expand to involve additional tissue at a
rapid rate that can approach several cm per hour. This necessitates multiple rounds of aggressive
and disfiguring surgical interventions, including debridement, fasciotomy and even amputation of
limbs and this lack of therapeutic options results in high mortality. An important gap in our
treatment arsenal is the lack of therapies to mitigate tissue damage during severe invasive
disease, which would improve the efficacy of antibiotic treatment to promote clearance of the
infection. The goal of this study is to explore proof-of-principle that therapeutic manipulation of
streptococcal pyruvate metabolism can provide a viable strategy for mitigation of tissue damage
to improve treatment outcomes of severe, invasive S. pyogenes disease. This concept builds
upon our preliminary data that suggests S. pyogenes employs its several alternative pathways for
pyruvate reduction to actively manipulate the host’s “Disease Tolerance” response to promote
its ability to infect diverse host niches. Disease tolerance is the process the host employs to
balance pathogen growth against the collateral damage to host tissues that accompanies immune
responses, known as Growth/Damage Balance. Through identification of host cells and relevant
signaling pathways that control disease tolerance, a therapeutic approach that targets microbial
metabolic and host cell signaling pathways can reduce damage to tissue to improve the ability of
antibiotics to clear infections.

## Key facts

- **NIH application ID:** 10452033
- **Project number:** 1R21AI163825-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael G. Caparon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,250
- **Award type:** 1
- **Project period:** 2022-01-05 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452033

## Citation

> US National Institutes of Health, RePORTER application 10452033, Novel Therapeutic Approach to Invasive Group A Streptococcal Disease (1R21AI163825-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10452033. Licensed CC0.

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