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New Papers Detail Complexity of Methylome-Related Virulence in Human Pathogens

Tuesday, September 30, 2014

In two new publications, one published today, scientists from Australia, Italy, the UK, and the US report critical and surprising new findings about DNA methylation-related complexity of bacteria. Adding to the list of advances from genome-wide epigenetic analysis, these projects enhance our understanding of how methylation systems work in human pathogens — and offer important clues for future investigations into how to treat them.

Today’s paper, “A random six-phase switch regulates pneumococcal virulence via global epigenetic changes,” was published in Nature Communications by scientists at the University of Leicester, University of Siena, University of Adelaide, and Griffith University. Senior authors Marco Oggioni and Michael Jennings and their collaborators studied Streptococcus pneumoniae, a bacterium responsible for serious infectious diseases including pneumonia, to figure out how the organism shifts between relatively benign and highly pathogenic phases.

To analyze the pathogen’s methylome, the scientists used Single Molecule, Real-Time (SMRT®) Sequencing. They found six different biological phases of the organism, each associated with a different level of virulence and characterized by a distinctive methylation pattern. Perhaps most importantly, they also found a genetic switch that enables S. pneumoniae cells to be randomly assigned to one of these six phases. “We show that the underlying mechanism for such phase variation consists of genetic rearrangements in a Type I restriction-modification system,” the authors write. They posit that the system is a key regulatory element designed to help the organism adapt to different host niches.

Now that scientists have determined the methylation profiles with the PacBio® platform, it should be possible for other scientists to accurately assign the pathogen to its specific phase. “Future studies must recognize the potential for switching between these heretofore undetectable, differentiated pneumococcal subpopulations in vitro and in vivo,” the authors note. “We believe these findings represent a new paradigm in gene regulation in bacteria and therefore are of great significance to the infectious disease field.”

Marco Oggioni said that dealing with S. pneumoniae’s genetic switch “is like being simultaneously confronted with six different bacteria; it gives them an unfair advantage, but knowing the genetic basis now places us in an optimal position to reinvestigate drug and vaccine efficacy.”

A separate paper from scientists at Griffith University and the Research Institute at Nationwide Children’s Hospital also looks at phase variation in a bacterium. “ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media” came out in The FASEB Journal earlier this month.

In it, senior author Kate Seib and her collaborators describe using SMRT Sequencing to characterize the methylome of Moraxella catarrhalis, a bacterium associated with childhood ear infections and complications of chronic obstructive pulmonary disease. The analysis revealed critical information about pathogenicity and its link to a phase-variable methyltransferase. Follow-up proteomic studies suggest that the phasevarion regulates expression in genes linked to infection, colonization, and defense against host organisms. “The modulation of gene expression via the ModM [phasevarion], and the significant association of the modM3 allele with otitis media, suggests a key role for ModM phasevarions in the pathogenesis of this organism,” the authors report.

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