Author(s): Luchang Zhu 1 , Gee W Lau 2 *
competence regulon; competence stimulating peptide; horizontal gene transfer; vaccine; virulence
The quorum sensing (QS) system allows bacteria to communicate with each other, share the information about cell density and adjust the gene expression pattern accordingly in response to changes in environmental cues. Among the most important class of genes regulated by QS are the virulence genes. The equivalence of the QS system in the Gram-positive pathogen Streptococcus pneumoniae (pneumococcus) is the competence regulon, controlled by a small-peptide pheromone called competence stimulating peptide (CSP). A unique aspect of the competence regulon in pneumococcus resides within its dual-faceted regulatory nature, controlling both the genetic transformation and, hence, the potential spread of antibiotic resistance genes, as well as virulence. Here, we review how the pneumococcal competence regulon controls genetic transformation and virulence, and discuss its therapeutic potential.
Pneumococcal competence regulon is responsible for genetic transformation and potential spread of antibiotic resistance genes
The major upstream players of the pneumococcal competence regulon are ComA  , CSP  , ComD  , ComE  and ComX  . CSP is a 17aa long peptide pheromone secreted by pneumococcus to activate the competence regulon. ComA is a membrane-associated peptide permease responsible for CSP maturation and export. CSP binds the membrane-localized histidine kinase receptor ComD. ComD autophosphorylates, then subsequently phosphorylates the cognate transcriptional regulator ComE  . ComE initiates the transcription of a set of 24 genes (early genes), including the alternative sigma factor ComX. In turn, ComX positively regulates the transcription of approximately 80 'late' genes, some of which encode effectors for DNA uptake and recombination  . Of these, the cgl operon encodes a pseudopilus structure. With corporation of other competent proteins, the pseudopilus forms a DNA uptake apparatus for the initial attachment of extracellular DNA to the pneumococcal surface. Attached DNA molecules are further processed by the membrane endonuclease EndA and internalized for integration. While conjugative elements appear to be important for the spread of antibiotic resistance genes in pneumococcus  , competence regulon-mediated horizontal gene transfer also plays a role  . For example, Marks et al . showed that high levels of the genetic recombination rate could be observed during pneumococcal nasopharyngeal carriage, with transformation efficiency during co-colonization by multiple strains as high as around 10-2  . Importantly, antibiotic stress has been purported to induce a CSP-ComD-dependent genetic transformation in pneumococcus  . This suggests that under certain in vivo circumstances, instead of being killed, pneumococcus could actively exploit the opportunity of antibiotic stress to acquire exogenous genes. Thus, strategies to suppress competence in pneumococcus may limit the spread of antibiotic resistance and virulence genes, especially when patients are undergoing antibiotic therapy.
Competence regulon is important for pneumococcal diseases
Importantly, in recent years, the competence regulon of pneumococcus has been shown to cross-regulate virulence. For example, Lau et al . were the first to report that a loss of function in ComB, an accessory protein to the ComA ABC transporter required for the export of CSP, as well as in the ComD histidine kinase, attenuates...