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J. Bacteriol. doi:10.1128/JB.01256-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Genetic Characterization and Virulence Role of the RALP3/LSAP Locus Upstream of the Streptolysin S Operon in Invasive M1T1 Group A Streptococcus

Department of Pediatrics, Division of Pharmacology & Drug Discovery, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; Department of Microbiology & Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Research Center, Veterans Affairs Medical Center, Memphis, TN 38104

^* To whom correspondence should be addressed. Email: vnizet{at}ucsd.edu.

	Abstract

Group A Streptococcus (GAS) is a leading human pathogen associated with a wide spectrum of mucosal and invasive infections. GAS express a large number of virulence determinants whose expression under control of several transcriptional regulatory networks. Here we perform the first mutational analysis of a genetic locus immediately upstream of the streptolysin S biosynthetic operon in several GAS genome sequences including that of the M1T1 serotype, the leading isolates associated with serious invasive disease. The locus consisting of a predicted RofA-like stand-alone transcriptional regulator (RALP3) and the largest open reading frame in the GAS genome, encoding a predicted LPXSG-motif cell wall anchored protein we have named LSAP (for large-surface anchored protein). Comparative RT-PCR analysis of WT M1T1 GAS and an isogenic RALP3-deficient mutant identifies RALP3 as a global transcriptional regulator affecting expression of numerous virulence factor genes, including strong repression of hyaluronic acid capsule and cysteine protease production. RALP3 contributed to GAS epithelial cell invasion and bloodstream survival. LSAP was found to be under negative regulation by RALP3 and influence GAS epithelial cell interactions and antimicrobial peptide sensitivity. Isogenic M1T1 GAS mutants lacking either RALP3 or LSAP were attenuated in a murine model of systemic infection, indicating this locus plays a role in the virulence potential of the organism.

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