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Infection and Immunity, October 2008, p. 4659-4668, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00597-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

TrxR, a New CovR-Repressed Response Regulator That Activates the Mga Virulence Regulon in Group A Streptococcus{triangledown} ,{dagger}

Temekka V. Leday,1,{ddagger} Kathryn M. Gold,2,{ddagger} Traci L. Kinkel,1,2 Samantha A. Roberts,3,§ June R. Scott,3 and Kevin S. McIver1,2*

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,1 Department of Cell Biology and Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742,2 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 303223

Received 15 May 2008/ Returned for modification 10 July 2008/ Accepted 24 July 2008

Coordinate regulation of virulence factors by the group A streptococcus (GAS) Streptococcus pyogenes is important in this pathogen's ability to cause disease. To further elucidate the regulatory network in this human pathogen, the CovR-repressed two-component system (TCS) trxSR was chosen for further analysis based on its homology to a virulence-related TCS in Streptococcus pneumoniae. In a murine skin infection model, an insertion mutation in the response regulator gene, trxR, led to a significant reduction in lesion size, lesion severity, and lethality. Curing the trxR mutation restored virulence comparable to the wild-type strain. The trxSR operon was defined in vivo, and CovR was found to directly repress its promoter in vitro. DNA microarray analysis established that TrxR activates transcription of Mga-regulated virulence genes, which may explain the virulence attenuation of the trxR mutant. This regulation appears to occur by activation of the mga promoter, Pmga, as demonstrated by analysis of a luciferase reporter fusion. Complementation of the trxR mutant with trxR on a plasmid restored expression of Mga regulon genes and restored virulence in the mouse model to wild-type levels. TrxR is the first TCS shown to regulate Mga expression. Because it is CovR repressed, TrxR defines a new pathway by which CovR can influence Mga to affect pathogenesis in the GAS.

* Corresponding author. Mailing address: Department of Cell Biology and Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742-4451. Phone: (301) 405-4136. Fax: (301) 314-9489. E-mail: kmciver{at}umd.edu

{triangledown} Published ahead of print on 4 August 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Camilli

{ddagger} T.V.L. and K.M.G. contributed equally to the manuscript.

§ Present address: Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD 29852.

Infection and Immunity, October 2008, p. 4659-4668, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00597-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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