# Impact of regulatory cross-talk on the pathophysiology of emergent acapsular group A streptococcus

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $243,000

## Abstract

PROJECT SUMMARY
The hyaluronic acid capsule of the major human pathogen group A Streptococcus (GAS) has classically been
considered essential to infectivity. GAS is divided into emm types based on variation in the emm gene that
encodes for the cell-surface, anti-phagocytic M protein. It has recently been appreciated that GAS strains from
emm types lacking capsule are increasingly causing serious human infections to the point where some 30% of
invasive GAS isolates are acapsular. How acapsular GAS causes infection is not currently known although it
has been postulated that acapsular GAS strains elaborate high levels of a key cytotoxin, streptolysin O (Slo).
Contrary to this conjecture, we have found that multiple acapsular emm types do not produce high levels of Slo,
and thus the long term goal of our research is to elucidate the mechanistic basis of acapsular GAS
pathophysiology. Through a comparative genomics approach, we have identified that acapsular GAS emm
types have distinct compositions of the promoters of mga and emm which encode the key transcriptional
regulator multi-gene activator (Mga) and M protein, respectively. Moreover, we have discovered that the control
of virulence (CovRS) two-component gene regulatory system specifically impacts mga and emm transcript levels
in acapsular relative to encapsulated GAS. These, and other, findings set the stage for this proposal which
seeks to test the hypothesis that mga and emm promoter composition are critical to the infectivity of acapsular
GAS by allowing for regulation by CovRS, which is critical for GAS to sense and respond to host signals. In
specific aim 1, we will determine how variation in mga and emm promoters of acapsular GAS compared to
encapsulated GAS alters the composition of the cell surface of acapsular emm4 and emm89 strains in response
to the human antimicrobial peptide LL-37. We will also assess the impact of mga and emm promoter composition
on acapsular GAS adherence to human epithelial cells and human extracellular matrix components, survival in
human blood, resistance to phagocytosis, and virulence in a mouse model. In specific aim 2, we will determine
if the changes observed in the mga and emm promoters of acapsular GAS allow for direct regulation by CovR
and is the mechanism by which CovS inactivation influences mga and emm transcript levels. We will investigate
in vivo interaction of CovR with mga and emm promoters and attempt to identify promoter regions that are key
to CovR-based regulation using a luciferase based reporter system. We also will assess whether CovR directly
represses emm in acapsular GAS independent of Mga. Completion of the research outlined herein will
significantly augment understanding of the molecular mechanisms underlying the emergence of acapsular GAS
which are a major cause of GAS infection yet remain poorly understood relative to encapsulated strains.

## Key facts

- **NIH application ID:** 10301505
- **Project number:** 1R21AI156202-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** SAMUEL A SHELBURNE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2021-07-12 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301505

## Citation

> US National Institutes of Health, RePORTER application 10301505, Impact of regulatory cross-talk on the pathophysiology of emergent acapsular group A streptococcus (1R21AI156202-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10301505. Licensed CC0.

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