Streptococcal virulence regulation by a novel intercellular signaling pathway

Methodist Hospital Research Institute, Houston TX

Investigators

Abstract

Group B streptococcus (GBS) is a major human pathogen that causes significant morbidity and mortality. GBS infections are the leading cause of stillbirths, preterm births, and neonatal mortality worldwide. Owing to the lack of a human vaccine and rise in antibiotic resistance among GBS strains, the clinical utility of current GBS infection control measures is significantly compromised. Thus, new approaches and/or targets are urgently required to treat or prevent GBS infections. In the proposed study, we seek to characterize a previously unknown intercellular signaling pathway and determine its contribution to GBS pathogenesis. Recently, we discovered a broadly distributed, novel intercellular signaling pathway in firmicutes that is comprised of a new class of bacterial intercellular signals, leaderless communication peptides (LCPs), and a cognate intracellular receptor that controls virulence gene expression in concert with LCP. Without exception, the cognate intracellular LCP receptors for all the identified LCPs belong to a subfamily of the Rgg/Rap/NprR/PlcR/PrgX/AimR (RRNPPA)-super family of peptide-sensing transcription regulators, the Rgg subfamily. As a result, the possibility that LCPs act as signals for the members of other subfamilies of RRNPPA regulators is unexplored, and the potential roles of an entirely new class of LCPs in bacterial group behaviors remain under appreciated. Our preliminary data uncover a previously unknown AimR subfamily regulator and a corresponding LCP in the GBS genome that likely controls the expression of genes encoding a putative toxin and toxin-associated transporters. However, the critical knowledge regarding the components of GBS LCP signaling pathway, molecular mechanism of GBS LCP signaling, and the contribution of LCP signaling pathway and LCP-controlled putative toxin to GBS pathogenesis are yet to be elucidated. Thus, the primary objective of the proposal is to dissect the signaling mechanism of AimR-LCP pair of GBS, elucidate its regulatory activity in vivo, and determine its contribution to GBS pathogenesis. We will test the central hypothesis of the proposal that AimRgbs-LCPgbs constitute a cytosolic receptor-LCP pair that mediates intercellular signaling and controls virulence-associated traits of GBS in two specific aims. The completion of this study will provide critical insights into the role of a novel intercellular signaling pathway in the survival and virulence of a human pathogen and potentially identify novel targets for future translational strategies to treat or prevent GBS infections.