Streptococcus pyogenes (group A streptococcus [GAS]), a multiple-
amino-acid-auxotrophic human pathogen, may face
starvation for
essential amino acids during various stages of the
infection process. Since the response of GAS to such conditions is likely to influence pathogenetic processes, we set out to identify by transcriptional analyses genes and operons that are responsive to
amino acid starvation and examined whether functionally meaningful response patterns can be ascertained. We discovered that GAS are capable of mounting a relA-independent
amino acid starvation response that involves transcriptional modulation of a wide array of housekeeping genes as well as accessory and dedicated virulence genes. Housekeeping genes that were upregulated during
starvation of both wild-type and relA mutant strains included the newly identified T-box members of the
aminoacyl-tRNA synthetase genes, the genes for components of the
tmRNA-mediated
peptide tagging and proteolysis system for abnormal
proteins (ssrA,
smpB, clpP, and clpC), and the operons for the dnaK and groE groups of
molecular chaperones. In addition to upregulation of the genes for
oligopeptide permease (
opp), intracellular
peptidase (pepB), and the two-component regulator covRS reported previously (K. Steiner and H. Malke, Mol. Microbiol. 38:1004-1016, 2000),
amino acid starvation stimulated the transcription of the growth phase-associated, virulence-regulatory fas operon, the
streptolysin S operon (sag), and the gene for autoinducer-2 production
protein (luxS). A prominent feature of operons exhibiting internal transcriptional termination (
opp, fas, and sag) was
starvation-promoted full-length transcription, a mechanism that improves the efficacy of these systems by increasing the level of coordinate transcription of functionally related genes. Based on these results, a regulatory network with feedback mechanisms is proposed that counteracts the stringent response, links the levels of key rate-limiting
enzymes to virulence gene expression, and enables the organism in a dynamic way to take advantage of
protein-rich environments provided by its human host. As several of the affected target genes are controlled by more than one regulator, fine modulation may result in accordance with the demands imposed by ecologically different colonization sites upon the adaptive capacity of the pathogen.