Title: Epigenetic regulation of gene expression in highly virulent group B streptococci
Funder: The Academy of Medical Sciences

Abstract: The overarching aim of this project is to define the role of DNA methylation in driving the hyper-virulence phenotype associated with serotype III ST17 (III_17) group B Streptococcus (GBS), specifically by characterising its impact on modulation of gene expression. Bacterial methyltransferases are often encoded as part of restriction modification systems (RMS), and I have identified two novel RMS strongly associated with III_17. RNAseq, in combination with SMRT sequencing, will be performed to define the methylation-dependent transcriptome of III_17 isolates. Isogenic mutants of differentially expressed virulence determinants will be generated, and characterised using a panel of assays quantifying bacterial colonisation and innate immune evasion established within my lab. GBS is an opportunistic pathogen that asymptomatically colonises up to 30% of the human population, and presents clinically as a leading cause of bacterial meningitis in neonates, with a case fatality of 15%. Understanding the bacterial drivers facilitating the establishment of invasive disease, including modulation of gene expression profiles, is thus critical for development of effective interventions. Novel sequencing techniques have alleviated the technical limitations associated with detection of DNA methylation, facilitating the current rapid expansion of research into the association between epigenetic modification and differential gene expression in bacterial pathogens. The III_17 GBS lineage exhibits unusually high virulence and disproportionately high incidence of neonatal meningitis, yet despite decades of research, the underlying basis for this is unknown. By defining the methylation-dependent transcriptome of III_17 strains I aim to better define the molecular basis for disease, ultimately informing design of effective control measures.

Lay abstract: The bacterium Group B Streptococcus (GBS) is a leading cause of meningitis in newborn babies, which can be lethal in up to 15% of cases. Despite this, GBS is normally found colonising healthy adults with no adverse symptoms. A group of GBS, called serotype III_ST17, causes a disproportionate amount of life-threatening disease, but we do not know why. In this project I aim to work out what makes this group more deadly than other GBS. One of the ways that GBS become more deadly is to increase the production of structures allowing them to hide from or fight off the human immune system. They can do this by modifying their DNA to change how well it serves as a blueprint for production of these structures. This does not change the DNA sequence, but alters how it is read. I have identified two new systems in serotype III_ST17 GBS that I predict will affect the DNA modification process, giving this group the upper hand against the human immune system. The aim of this project is to work out how the production of bacterial structures is altered by each of these systems. We then intend to work out how specific bacterial structures help the bacteria to cause disease in humans. Antibiotics are not always successful in treating invasive GBS disease, therefore it is important to carry out studies like this to understand how the bacterium can switch from benign to invasive states, enabling us ultimately to design better treatments and vaccines.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION