Investigations into the Role of Inter and Intra Strain Quorum Sensing in Pneumococcal Pathogenesis

Streptococcus pneumoniae is the leading cause of pediatric morbidity and mortality worldwide. The rich genomic diversity among strains of pneumococci contributes to varied phenotypes exhibited by strains such as propensity to cause disease, colonization capabilities, and responses to antibiotics and vaccines. In this thesis, I explore the role of genes acquired by gene transfer on the ability of pneumococcus to cause disease in single and multi-strain infections. I describe my work on the identification and molecular characterization of a novel quorum sensing system comprising a transcription regulator and peptide (TprA2/PhrA2). This system is unique to the PMEN1 lineage, a group of pandemic and multi-drug resistant pneumococcal strains. I demonstrate the detailed mechanism of regulation of this peptide-regulator pair and its ability to control a downstream lanthionine-containing peptide. Through in vivo studies I observe that the TprA2 regulator acts to promote commensalism over tissue dissemination. In addition, I show that the downstream lanthionine-containing peptide is a novel virulence determinant. My findings extend beyond this specific cell-cell communication system, since PhrA2 unidirectionally influences gene expression of a second quorum sensing system, TprA/PhrA, widespread across the pneumococcal species. I participated in studies that conclusively demonstrate the role of TprA/PhrA as a potent virulence determinant, and I show that the PMEN1-unique peptide PhrA2 can control gene expression of TprA/PhrA in a non-PMEN1 strain. These data open the door to the potential role for PMEN1 strains in modifying the virulence potential of other strains in multi-strain infections. In summary, my findings suggest that a horizontally acquired PMEN1-unique genomic element has the ability to modify regulatory circuits and fine tune the net regulation of multiple downstream effectors via intra- and inter-strain communication in single and multi strain infections.