The human pathogens Streptococcus pneumoniae and Streptococcus mutans have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural transformation. Natural transformation provides bacteria with a mechanism to repair damaged genes or as a source of new advantageous traits. In S. pneumoniae, the competence pathway is controlled by the two-component signal transduction pathway ComCDE, which directly regulates SigX, the alternative sigma factor required for the initiation into competence. Over the past two decades, effectors of cellular killing (i.e., fratricides) have been recognized as important targets of the pneumococcal competence QS pathway. Recently, direct interactions between the ComCDE and the paralogous BlpRH pathway, regulating bacteriocin production, were identified, further strengthening the interconnections between these two QS systems. Interestingly, a similar theme is being revealed in S. mutans, the primary etiological agent of dental caries. This review compares the relationship between the bacteriocin and the competence QS pathways in both S. pneumoniae and S. mutans, and hopes to provide clues to regulatory pathways across the genus Streptococcus as a potential tool to efficiently investigate putative competence pathways in nontransformable streptococci.

Natural transformation, or competence, is an ability inherent to bacteria for the uptake of extracellular DNA. This process is central to bacterial evolution and allows for the rapid acquirement of new traits, such as antibiotic resistance in pathogenic microorganisms. For the Gram-positive bacteria genus Streptococcus, genes required for competence are under the regulation of quorum sensing (QS) mediated by peptide pheromones. One such system, ComRS, consists of a peptide (ComS) that is processed (XIP), secreted, and later imported into the cytoplasm, where it binds and activates the transcription factor ComR. ComR then engages in a positive feedback loop for the expression of ComS and the alternative sigma-factor SigX. Although ComRS are present in the majority of Streptococcus species, the sequence of both ComS/XIP and ComR diverge significantly, suggesting a mechanism for species-specific communication. To study possible cross-talk between streptococcal species in the regulation of competence, and to explore in detail the molecular interaction between ComR and XIP we undertook an interdisciplinary approach. We developed a ‘test-bed’ assay to measure the activity of different ComR proteins in response to cognate and heterologous XIP peptides in vivo, revealing distinct ComR classes of strict, intermediate, and promiscuous specificity among species. We then solved an X-ray crystal structure of ComR from S. suis to further understand the interaction with XIP and to search for structural features in ComR proteins that may explain XIP recognition. Using the structure as a guide, we probed the apo conformation of the XIP-binding pocket by site-directed mutagenesis, both in test-bed cultures and biochemically in vitro. In alignments with ComR proteins from other species, we find that the pocket is lined by a variable and a conserved face, where residues of the conserved face contribute to ligand binding and the variable face discriminate among XIP peptides. Together, our results not only provide a model for XIP recognition and specificity, but also allow for the prediction of novel XIP peptides that induce ComR activity. Bacteria transmit chemical signals to each other in a process known as quorum sensing. This adaptation is central to pathogenesis as it allows bacteria to coordinate a group response, such as when to form a biofilm, secrete virulence factors, or uptake new DNA. Quorum sensing in many species of Gram-positive bacteria utilizes secreted short peptide signals that are sensed by protein receptors that alter gene expression. The ComR-ComS receptor-signal pair is a regulator of competence for genetic transformation that is broadly conserved in a majority of Streptococcus species, including those pathogenic in humans and animals. Despite this conservation, we observe sequence diversity among ComRS orthologs that raises questions relating to sensory specificity and the molecular mechanism of peptide recognition. To address this, we directly tested the possibility for signaling cross-talk and identified three general categories of ComR receptors displaying strict, intermediate, and promiscuous responses to heterologous peptides. To elucidate the molecular mechanism of receptor specificity we determined an X-ray crystal structure of ComR from S. suis. We observe a conserved face of the ligand pocket important for peptide binding and a variable face that functions in peptide specificity. Finally, basic criteria necessary for peptide responses were used to redesign active peptides from inactive templates.

Emerging evidence has demonstrated that perturbations of host-microbial interactions by pathogens can lead to an altered microenvironment that promotes tumorigenesis. A recent study provides new evidence and mechanisms on how repetitive exposure to non-Typhoidal Salmonella (NTS) increases the risk for colon cancer. This study integrated a serological and epidemiological approach with both in vivo and in vitro analyses, showed that the magnitude of exposure to NTS is associated with colonic tumorigenesis. In vivo exposure to repetitive low doses of NTS led to colonic tumors similar as a single high NTS dose in mice. Repetitive NTS infections significantly increase the proliferation of transformed cells in tissue cultures. The research results open new possibilities for the diagnosis, prevention, and treatment of colon cancer. The unanswered questions remain, including validation of the current findings in other cohorts, differences in lifestyle, and changes of gut microbiome after Salmonella infection. Salmonellae exposure can be limited by eating cooked meats and washing vegetables well. It is necessary to develop guidelines and criteria for screenings and follow-ups in people with exposure history to Salmonella and other cancer-associated pathogens.