Connecting The Dots From Competence To Pneumococcal Disease

In 1928, Frederick Griffith was in search of a vaccine to protect against the pneumococcus, one of the major human bacterial pathogens. Instead, this English army doctor uncovered the transformation principle. He observed a non-pathogenic clone become lethal in the presence of dead pathogenic pneumococcus. Serendipitously, he had captured the uptake of DNA by bacteria.

Almost a century later, with thousands of bacterial genomes sequenced, researchers have observed the extensive movement of DNA across numerous species. A notable consequence of this transfer is the emergence of “superbugs,” a consequence of the movement of drug-resistant genes across bacteria. The modern-day epidemic of multi-drug resistant bacteria has emerged as one of the top threats to modern civilization.

The process of DNA uptake has been extensively studied in the pneumococcus. Via seminal works, we now know that uptake of DNA is triggered by a small molecule and coordinated via a multistep pathway known as competence. This pathway plays an important role in population-level decisions, which occur in microbial community structures termed biofilms. Once triggered, the competence pathways signals cells to uptake DNA and incorporate novel genetic material into their genomes. Remarkably, the competence pathway extends well beyond its control of DNA uptake; once triggered, it coordinates an estimated ten percent of the bacterial genes. Activation of competence is associated with an increase in the size of biofilms and exacerbation of disease for the human host. Our recent study reveals a new molecule, which we have termed BriC, as a new player in this complex pathway.

BriC is a small protein that is activated by the induction of competence. We show that BriC is secreted by the cells and serves as a signal in biofilms, where it connects competence with infection outcome. Specifically, BriC is a key player in the development of biofilms, where it serves as a molecular link between competence activation and the increase in the size of the biofilm community. BriC also functions as a colonization factor, as its expression is associated with the ability of pneumococcus to colonize and survive in the upper airways. Thus, this characterization of BriC reveals a missing link in the chain that connects the induction of competence to biofilm development.

BriC is not only part of a signaling cascade that promotes gene exchange, but it is also a target of genomic plasticity. Our analysis of hundreds of pneumococcal genomes revealed a variation in the briC promoter. A promoter is a region that controls the timing and extent to which a gene product is produced. Strains belonging to many of the most clinically relevant pneumococcal lineages contain a longer briC promoter, distinguished by the presence of a repetitive insertion sequence. This genomic modification has functional and biological implications. It leads to an increase in the levels of briC expression and provides a means for activation of briC in a competence-independent manner. We propose that competence-independent induction of briC is an elegant evolutionary solution to activate a subset of competence genes without expending the metabolic energy required to turn on the entire pathway.

Molecules that serve as signals in biofilms, such as BriC, are candidate targets for therapeutic development. This is particularly relevant to cells growing in a biofilm.

Not only do pneumococcal biofilms contribute to increased colonization and pathogenesis, but cells in this mode of growth are highly recalcitrant to antibiotic treatment. The discovery of signaling molecules that influence disease present exciting prospects for the development of novel therapeutics.

These findings are described in the article entitled Function of BriC peptide in the pneumococcal competence and virulence portfolio, recently published in the journal PLOS Pathogens.

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