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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 ^,

Temekka V. Leday,^1, Kathryn M. Gold,^2, Traci L. Kinkel,^1,2 Samantha A. Roberts,^3, June R. Scott,³ and Kevin S. McIver^1,2*

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.

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* 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

Published ahead of print on 4 August 2008.

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

Editor: A. Camilli

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.

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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.

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