Streptococcal virulence regulation by a novel intercellular signaling pathway - group b streptococcus (GBS) is a major human pathogen that causes significant morbidity and mortality

The National Institute of Allergy and Infectious Diseases (NIAID) awarded The Methodist Hospital Research Institute a Project Grant of $444,125 under the Allergy and Infectious Diseases Research program (CFDA 93.855) on August 8, 2025, with a completion date of July 31, 2027. This research project will characterize a previously unknown intercellular signaling pathway in Group B Streptococcus (GBS) and determine its contribution to bacterial pathogenesis. Specifically, the research will investigate leaderless communication peptides (LCPs) and their cognate intracellular receptors that control virulence gene expression, with particular focus on an AIMR subfamily regulator and corresponding LCP in the GBS genome that likely regulate genes encoding putative toxins and toxin-associated transporters.

The primary deliverables of this award include comprehensive characterization of GBS LCP signaling pathway components, elucidation of the molecular mechanisms underlying GBS LCP signaling, and determination of the contribution of LCP signaling and LCP-controlled putative toxins to GBS pathogenesis. This research addresses a critical public health need, as GBS is a major human pathogen responsible for significant morbidity and mortality, including being the leading cause of stillbirths, preterm births, and neonatal mortality worldwide. By identifying novel signaling pathways and virulence mechanisms, this research seeks to provide new therapeutic targets and approaches for treating or preventing GBS infections, particularly given the lack of effective human vaccines and rising antibiotic resistance among GBS strains.

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.