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In Bacterial Study, Scientists Link Epigenetic Switch to Virulence, Antibiotic Resistance, and More

Wednesday, August 26, 2015

Scientists from Griffith University, Ohio State University College of Medicine, and other institutions recently published a detailed study of phase-variable expression of a DNA methyltransferase in non-typeable Haemophilus influenzae, the predominant cause of pediatric middle ear infections. The team found that the bacterium’s epigenetic switch regulates proteins used in current vaccine candidates and influences important traits including antibiotic resistance, ability to evade the host immune system, and biofilm formation, which significantly contributes to chronic infection.

The paper, “A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae,” was published in Nature Communications last month by lead author John Atack, senior author Michael Jennings, and colleagues. Their study of H. influenzae used SMRT® Sequencing to elucidate the genome and epigenome of multiple bacterial strains collected across several decades. Closed genome assemblies were generated for all five bacterial strains sequenced.

The scientists aimed to identify the DNA recognition motifs for the bacterium’s five known alleles of the N6-adenine DNA methyltransferase, ModA, which has been linked to random on/off switching. Atack and colleagues found that these phasevarions actively alter gene expression in every strain analyzed, and also successfully identified a novel allele in this system. Based on SMRT Sequencing data, most alleles were classified as having “prototypical type III methyltransferase recognition sequences,” but one allele was found to recognize a four-base motif instead of the traditional five.

The impact of this allele-specific epigenetic switch on bacterial pathogenesis and disease was examined in detail. The scientists demonstrated that these phasevarions influence bacterial susceptibility to a number of antibiotics, including ampicillin and erythromycin, which are commonly used to treat H. influenzae infection. The group discovered that these switches influence the protein expression of several potential vaccine candidates currently in development. They also report that phasevarions are prevalent in H. influenzae strains found in healthy people, not just those associated with chronic infections.

The scientists also investigated the influence of these alleles using a chinchilla model for ear infection, providing the first in vivo evidence for consistent selection of the “on” phenotype for one of the phasevarion alleles. “This indicates that switching of the modA2 phasevarion plays an important role in niche adaptation to the middle ear,” Atack et al. write.

These results demand additional study, the authors say. “Defining the stable immunological target that NTHi [H. influenzae] represents requires a full analysis of the impact of phasevarions on NTHi gene expression, and future vaccine candidates will need to be assessed to confirm that their expression is not influenced by the epigenetic changes that result from phasevarion ON/OFF switching,” they write. “Bacterial epigenetics is a key emerging field in bacterial pathogenesis and a new challenge to vaccine development for these important human pathogens.”

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