S. pyogenes is a strict human pathogen that causes diseases ranging from mild infections such as strep throat or impetigo to life threatening diseases like necrotizing fasciitis or toxic shock syndrome. Different disease manifestations seem to be caused by different types of regulation of virulence factors in different tissues; S. pyogenes uses many regulators including 11 - 13 two component systems and several stand-alone response regulators. Our future studies will be focused on the regulation of virulence factors such as the thermoregulation of capsule expression and regulation of CAMP factor expression as model systems for the virulence gene regulation by S. pyogenes. Another interest of our research is to study genes such as gidA and cvfA which are necessary for the virulence of S. pyogenes but whose functions are not well known. The S. pyogenes genome contains hundreds of genes whose functions are unknown.
Thermoregulation of Capsule Production. Streptococcus pyogenes is a human pathogen that infects many different tissues including skin, throat, blood, female urogenital tract, and lower gastrointestinal tract. These tissues exhibit different temperatures ranging from 25°C to 37°C. Thus, S. pyogenes is expected to control its physiology and the expression of virulence factors according to temperature variations in order to infect and survive in those tissues. During a study of the streptococcal capsule, we found that the capsule expression is thermoregulated; the capsule production by a S. pyogenes strain was higher at room temperature (20°C ~ 25°C) than that at 37°C. The capsule is one of the major virulence factors involved in the initial colonization on skin and throat and in the escape from the host immune system. Based on the phenotype of the temperature-regulated capsule production, we study the molecular mechanism of this thermoregulation.
CvfA Genomic analyses of multiple strains of Streptococcus pyogenes has revealed many conserved hypothetical genes whose function and contribution to virulence is unknown. In our study, transposon mutagenesis identified one conserved hypothetical gene known as cvfA as a regulator of the expression of several virulence genes. Mutants defective for cvfA were highly attenuated for virulence in a murine model of subcutaneous infection, consistent with a prior report of attenuation in other infection models (Kaito, et al. 2005. Mol Microbiol. 56:934-44). To gain insight into CvfA's function, global transcription profiling was conducted to compare wild type with a CvfA- mutant, revealing a conditional influence on the transcriptome dependent on growth phase and medium composition. The influence of cvfA was most pronounced during stationary phase following growth in media rich in peptides and poor in carbohydrates. Under these conditions, up to 30% of the transcriptome exhibited altered expression. Expression of the genes for multiple virulence factors were altered including those encoding streptokinase, CAMP factor, streptolysin O, M protein, mitogenic factor, and SpeB, as was confirmed by real time RT-PCR analyses.