A novel streptococcal cell–cell communication peptide promotes pneumococcal virulence and biofilm formation

Abstract

Streptococcus pneumoniae (pneumococcus) is a major human pathogen. It is a common colonizer of the human respiratory track, where it utilizes cell-cell communication systems to coordinate population-level behaviors. We reasoned that secreted peptides that are highly expressed during infection are pivotal for virulence. Thus, we used in silico pattern searches to define a pneumococcal secretome, and analyzed the transcriptome of the clinically important PMEN1 lineage to identify which peptide-encoding genes are highly expressed in vivo. In this study, we characterized virulence peptide 1 (vp1), a highly expressed Gly-Gly peptide-encoding gene in chinchilla middle ear effusions. The vp1 gene is widely distributed across pneumococcus as well as encoded in related species. Studies in the chinchilla model of middle ear infection demonstrated that VP1 is a virulence determinant. The vp1 gene is positively regulated by a transcription factor from the Rgg family and its cognate SHP (short hydrophobic peptide). In vitro data indicated that VP1 promotes increased thickness and biomass for biofilms grown on chinchilla middle ear epithelial cells. Further, the wild-type biofilm is restored with the exogenous addition of synthetic VP1. We conclude that VP1 is a novel streptococcal regulatory peptide that controls biofilm development and pneumococcal pathogenesis.

Pneumococcal attachment to epithelial cells is enhanced by the secreted peptide VP1 via its control of hyaluronic acid processing

“…We propose that VP1 serves as a marker for 48 colonization and a target for drug design. We have previously shown that vp1 plays a role in biofilm development (7). Thus, we 135 investigated whether vp1 influences attachment to epithelial cells, an early step in biofilm 136 formation.…”

“…60 61 Pneumococcus secretes many small peptides, which influence colonization, virulence, 62 and adaptation via effects on competence, intra-species competition, and biofilm development 63 (6-18). The Virulence Peptide 1 (VP1) is a member of a family of peptides with a conserved N-64 terminal sequence characterized by a double glycine motif, which directs its export into the 65 extracellular milieu via ABC transporters (7,19). The vp1 gene is widely distributed across 66 pneumococcal strains, as well as encoded in related streptococcal species.…”

“…The vp1 gene is widely distributed across 66 pneumococcal strains, as well as encoded in related streptococcal species. The gene 67 encoding VP1 is a virulence determinant and is highly upregulated in the presence of host cells 68where it promotes biofilm development (7,20). Pneumococcal biofilms have been documented 69 in the nasopharynx, the middle ear, and the sinus (21-24).…”

“…Our experiments in a murine model of pneumococcal carriage 127 demonstrate that both VP1 and HA processing promote colonization. We propose a model 128where the nutritional status of the host induces expression of the pneumococcal secreted 129 peptide VP1, via CodY and Rgg144 (7,18,58). Signaling by VP1 triggers HA metabolism in the 130 bacteria, which in turn, regulates attachment to host cells and colonization in the upper 131 airways.…”

“…where it promotes biofilm development (7,20). Pneumococcal biofilms have been documented 69 in the nasopharynx, the middle ear, and the sinus (21-24).…”