Streptococcus pneumoniae has been known to have something of a split personality since 1933, with one phase or phenotypic form adopting a “live and let live” lifestyle, and the other phase behaving rather more aggressively, which is to say virulently. Now it appears that S. pneumoniae has even more personalities, each associated with a different proclivity toward invasive, life-threatening disease. In fact, any of six personalities may emerge depending on the action of a single genetic switch.

To uncover the switch, an international team of scientists conducted a study in genomics, but they looked beyond nucleotide polymorphisms or accessory regions as possible phenotype-shifting mechanisms. Instead, they focused on the potential of restriction-modification (RM) systems to mediate gene regulation via epigenetic changes.

Scientists representing the University of Leicester, Griffith University’s Institute for Glycomics, the University of Adelaide, and Pacific Biosciences realized that the S. pneumoniae genome contains two Type I, three Type II, and one Type IV RM systems. Of these, only the DpnI Type II RM system had been described in detail. Switchable Type I systems had been described previously, but these reports did not provide evidence for differential methylation or for phenotypic impact.

As it turned out, the Type I system embodied a mechanism capable of randomly changing the bacterium’s characteristics into six alternative states. The mechanism’s details were presented September 30 in Nature Communications, in an article entitled, “A random six-phase switch regulates pneumococcal virulence via global epigenetic changes.”

“The underlying mechanism for such phase variation consists of genetic rearrangements in a Type I restriction-modification system (SpnD39III),” wrote the authors. “The rearrangements generate six alternative specificities with distinct methylation patterns, as defined by single-molecule, real-time (SMRT) methylomics.”

The SpnD39III variants, the authors continued, have distinct gene expression profiles. For example, Professor Michael Jennings, deputy director of the Institute for Glycomics at Griffith University, said, “By use of the latest DNA sequencing technology from Pacific Biosciences, we have shown that the pneumococcus generates subpopulations that have distinct DNA methylation patterns, and we have shown that these epigenetic changes alter both gene expression patterns and virulence.

“Each time this bacterium divides it is like throwing a dice. Any one of six different cell types can appear. Understanding the role this six-way switch plays in pneumococcal infections is key to understanding this disease and is crucial in the development of new and improved vaccines.”

“Future studies must recognize the potential for switching between these heretofore undetectable, differentiated pneumococcal subpopulations in vitro and in vivo,” the authors of the study concluded. “Similar systems exist in other bacterial genera, indicating the potential for broad exploitation of epigenetic gene regulation.”








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