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Background  D-alanylated lipoteichoic acid is a virtually ubiquitous component of Gram-positive cell walls. Mutations in the  dltABCD  operon of numerous species exhibit pleiotropic effects, including reduced virulence, which has been attributed to increased binding of cationic antimicrobial peptides to the more negatively charged cell surface. In this study, we have further investigated the effects that mutating  dltA  has on virulence factor expression in  Streptococcus pyogenes .    Methodology/Principal Findings  Isogenic Δ dltA  mutants had previously been created in two distinct M1T1 isolates of  S. pyogenes . Immunoblots, flow cytometry, and immunofluorescence were used to quantitate M protein levels in these strains, as well as to assess their ability to bind complement. Bacteria were tested for their ability to interact with human PMN and to grow in whole human blood. Message levels for  emm ,  sic , and various regulatory elements were assessed by quantitative RT-PCR. Cell walls of Δ dltA  mutants contained much less M protein than cell walls of parent strains and this correlated with reduced levels of  emm  transcripts, increased deposition of complement, increased association of bacteria with polymorphonuclear leukocytes, and reduced bacterial growth in whole human blood. Transcription of at least one other gene of the  mga  regulon,  sic , which encodes a protein that inactivates antimicrobial peptides, was also dramatically reduced in Δ dltA  mutants. Concomitantly,  ccpA  and  rofA  were unaffected, while  rgg  and  arcA  were up-regulated.    Conclusions/Significance  This study has identified a novel mechanism for the reduced virulence of  dltA  mutants of  Streptococcus pyogenes  in which gene regulatory networks somehow sense and respond to the loss of DltA and lack of D-alanine esterification of lipoteichoic acid. The mechanism remains to be determined, but the data indicate that the status of D-alanine-lipoteichoic acid can significantly influence the expression of at least some streptococcal virulence factors and provide further impetus to targeting the  dlt  operon of Gram-positive pathogens in the search for novel antimicrobial compounds.

Inactivation of DltA Modulates Virulence Factor Expression in Streptococcus pyogenes