Virulence control in group A<i>Streptococcus</i>by a two-component gene regulatory system: Global expression profiling and<i>in vivo</i>infection modeling

TLDR

Two‑component regulatory systems, such as the covRS system in Group A Streptococcus, modulate expression of virulence factors that enable the pathogen to survive and cause invasive disease in humans. The authors employed DNA microarrays and quantitative RT‑PCR to determine that CovR regulates transcription of 15 % of the GAS chromosome, including genes for surface proteins and secreted factors. Inactivation of covRS markedly increases virulence in mouse models, while CovR’s regulatory influence on 271 genes—many encoding virulence determinants and other transcriptional regulators—was confirmed, revealing differential expression during soft‑tissue infection and providing a genome‑scale view of the GAS virulence network.

Abstract

Two-component gene regulatory systems composed of a membrane-bound sensor and cytoplasmic response regulator are important mechanisms used by bacteria to sense and respond to environmental stimuli. Group A Streptococcus, the causative agent of mild infections and life-threatening invasive diseases, produces many virulence factors that promote survival in humans. A two-component regulatory system, designated covRS (cov, control of virulence; csrRS), negatively controls expression of five proven or putative virulence factors (capsule, cysteine protease, streptokinase, streptolysin S, and streptodornase). Inactivation of covRS results in enhanced virulence in mouse models of invasive disease. Using DNA microarrays and quantitative RT-PCR, we found that CovR influences transcription of 15% (n = 271) of all chromosomal genes, including many that encode surface and secreted proteins mediating host-pathogen interactions. CovR also plays a central role in gene regulatory networks by influencing expression of genes encoding transcriptional regulators, including other two-component systems. Differential transcription of genes influenced by covR also was identified in mouse soft-tissue infection. This analysis provides a genome-scale overview of a virulence gene network in an important human pathogen and adds insight into the molecular mechanisms used by group A Streptococcus to interact with the host, promote survival, and cause disease.