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

doi:10.1073/pnas.202353699

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

^*Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; ^†Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and ^§Department of Family and Community Medicine, Baylor College of Medicine, Houston, TX 77005

Edited by John J. Mekalanos, Harvard Medical School, Boston, MA, and approved July 31, 2002 (received for review June 12, 2002)

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.

microarrays‖real-time RT-PCR‖transcript analysis

Footnotes

↵ ‡ Present address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014.
↵ ¶ To whom correspondence should be addressed. E-mail: jmusser{at}niaid.nih.gov.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

GAS,

group A Streptococcus;

Cov/cov,

control of virulence;

ME,

mid-exponential;

LE,

late-exponential;

S,

stationary