# Macrophage Immunosuppression by Quorum-Induced Streptococcus pyogenes

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $690,493

## Abstract

Abstract
Macrophage Immunosuppression by Quorum-Induced Streptococcus pyogenes
The human-restricted pathosymbiont Streptococcus pyogenes (Group A Streptococcus, GAS) uses the
Rgg2/Rgg3 QS system to modify the bacterial surface, allowing coordination of biofilm formation and lysozyme
resistance. Preliminary findings demonstrate that innate immune cell responses to GAS are substantially altered
by the QS status of the bacteria. Published and preliminary data show that macrophage activation, stimulated
by multiple agonists and assessed by cytokine production and NFB activity, was substantially suppressed upon
interaction with QS-ON GAS but not QS-OFF bacteria. Neither macrophage viability nor bacterial adherence
were seen as different between QS activity states, yet TNF, IL-6, INF levels and an NFB reporter were
drastically lower when QS was ON. Suppression required contact between viable bacteria and macrophages. A
QS-regulated biosynthetic gene cluster (BGC) in the GAS genome, encoding several putative enzymes, was
also required for macrophage modulation. Newly acquired transcriptomic analysis (RNA-Seq) of macrophages
infected with QS-ON and QS-OFF GAS indicate clear divergence in gene expression patterns between infection
types. QS-OFF infections induce macrophage characteristics with signatures of classic activation (M1-like),
whereas QS-ON infections produced genetic signatures consistent with alternatively activated (M2-like)
macrophages, where metabolic pathways of oxidative phosphorylation and fatty acid beta-oxidation are induced.
We propose a model that upon contact with macrophages, QS-ON GAS produce a BGC-derived factor capable
of suppressing inflammatory responses. The suppressive capability of QS-ON GAS is abolished after treatment
with a specific QS inhibitor. These observations suggest that interfering with the ability of bacteria to collaborate
via QS can serve as a strategy to counteract microbial efforts to manipulate host defenses. This application
seeks to accomplish three primary objectives: 1) identify the QS-regulated factor generated by the BGC and the
biosynthetic intermediates; 2) identify the macrophage target and mechanism of NFB inhibition; and 3) evaluate
the physiological impact on immune cell activity and the advantage provided to GAS in vivo and in human explant
tissue models.

## Key facts

- **NIH application ID:** 10442806
- **Project number:** 1R01AI162679-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** MICHAEL J FEDERLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $690,493
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442806

## Citation

> US National Institutes of Health, RePORTER application 10442806, Macrophage Immunosuppression by Quorum-Induced Streptococcus pyogenes (1R01AI162679-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442806. Licensed CC0.

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