Function of BriC peptide in the pneumococcal competence and virulence portfolio

Abstract

Streptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that causes otitis media, sinusitis, pneumonia, meningitis and sepsis. The progression to this pathogenic lifestyle is preceded by asymptomatic colonization of the nasopharynx. This colonization is associated with biofilm formation; the competence pathway influences the structure and stability of biofilms. However, the molecules that link the competence pathway to biofilm formation are unknown. Here, we describe a new competence-induced gene, called briC, and demonstrate that its product promotes biofilm development and stimulates colonization in a murine model. We show that expression of briC is induced by the master regulator of competence, ComE. Whereas briC does not substantially influence early biofilm development on abiotic surfaces, it significantly impacts later stages of biofilm development. Specifically, briC expression leads to increases in biofilm biomass and thickness at 72h. Consistent with the role of biofilms in colonization, briC promotes nasopharyngeal colonization in the murine model. The function of BriC appears to be conserved across pneumococci, as comparative genomics reveal that briC is widespread across isolates. Surprisingly, many isolates, including strains from clinically important PMEN1 and PMEN14 lineages, which are widely associated with colonization, encode a long briC promoter. This long form captures an instance of genomic plasticity and functions as a competence-independent expression enhancer that may serve as a precocious point of entry into this otherwise competence-regulated pathway. Moreover, overexpression of briC by the long promoter fully rescues the comE-deletion induced biofilm defect in vitro, and partially in vivo. These findings indicate that BriC may bypass the influence of competence in biofilm development and that such a pathway may be active in a subset of pneumococcal lineages. In conclusion, BriC is a part of the complex molecular network that connects signaling of the competence pathway to biofilm development and colonization.

Molecular Determinants of Substrate Selectivity of a Pneumococcal Rgg-Regulated Peptidase-Containing ABC Transporter

“…The next step will be to study the corresponding sequence and structural motifs in PCATs that contribute to this selectivity. In addition to bacteriocins and quorum sensing (3), GG peptides have now been linked to biofilm formation, colonization of host niches, and dissemination during infection (18,46). Ultimately, the ability to predict and rationalize PCAT-GG peptide pairings will advance our understanding of a broad range of biologically significant microbial processes.…”

Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

“…Many of the steps in biofilm formation cross over into bacterial aggregation (discussed above) [31,32]. It is clear that the physiology of biofilms and virulence extends to changes in bacterial behavior such as competence and fratricide [33][34][35][36]. Many proteins and signaling molecules, such as PsrP, GlpO, BriC, CbpD, LytC, and CbpF, can be targeted to interrupt the participation of these processes in biofilms and colonization.…”

The pneumococcal social network

“…The best characterized pneumococcal double-glycine peptide is the competence-stimulating peptide (CSP) [ 18 ]. Other examples include the bacteriocin-inducing peptide (BIP) [ 19 ], the competence-induced bacteriocins (CibA and CibB) [ 20 ], peptides of the bacteriocin immunity region (BIR) [ 21 ], the virulence peptide 1 (VP1) [ 22 ], the biofilm-regulating peptide induced by competence (BriC) [ 23 , 24 ], peptides of the rtg locus [ 25 ], and LanA [ 22 , 26 ] ( Table 1 , S1 Table ). Furthermore, comparative genomic approaches have revealed additional double-glycine peptides that remain to be characterized [ 22 , 27 ].…”

“…These may impact development of biofilms or be associated with modifications in cell surface components such as membrane composition and capsule expression [ 22 , 23 , 43 ]. Cell–cell communication system behaviors may also be accompanied by modification in ability for DNA uptake, fratricide, or bactericidal activity [ 20 , 23 , 31 , 75 , 76 ]. These physiological changes may alter the propensity of cells to acquire antibiotic resistance genes and influence the emergence of vaccine-escape strains.…”