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Infect. Immun. doi:10.1128/IAI.00343-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CcpA-mediated Repression of Streptolysin S Expression and Virulence

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9048; Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742-4451

^* To whom correspondence should be addressed. Email: kmciver{at}umd.edu.

	Abstract

CcpA is the global mediator of carbon catabolite repression (CCR) in Gram-positive bacteria and growing evidence from several pathogens, including the group A streptococcus (GAS), suggests that CcpA plays an important role in virulence gene regulation. In this study, a deletion of ccpA in an invasive M1 GAS was used to test the contribution of CcpA to pathogenesis in mice. Surprisingly, the ccpA mutant exhibited a dramatic "hypervirulent" phenotype compared to the parental MGAS5005 strain reflected as increased lethality in a model of systemic infection (i.p.) and larger lesion size in a model of skin infection (s.c.). Expression of ccpA in trans from its native promoter was able to complement both phenotypes, suggesting that CcpA was acting to repress virulence in GAS. To identify the CcpA regulated gene(s) involved, a transcriptome analysis was performed on mid-logarithmic cells grown in rich media. CcpA was found to primarily repress 6% of the GAS genome (127 genes), including those involved in sugar metabolism, transcriptional regulation, and virulence. Notably, the entire sag operon necessary for Streptolysin S (SLS) production was under CcpA-mediated CCR, as was SLS hemolytic activity. Purified CcpA-His bound specifically to a cre within PsagA, demonstrating direct repression of the operon. Finally, SLS activity is required for the increased virulence of a ccpA mutant during systemic infection, but did not affect virulence in a wild type background. Thus, CcpA acts to repress SLS activity and virulence during systemic infection in mice, revealing an important link between carbon metabolism and GAS pathogenesis.

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