Investigating the genetic basis for bacterial toxin production using functional genomics

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Streptococcus pneumoniae is both a commensal inhabitant of the human nasopharynx, and an opportunistic pathogen which can cause serious respiratory disease in the form of pneumoniae, meningitis and septicaemia in people with compromised immunity. Particularly dangerous to the very young and the very old, this pathogen has proved hard to control through vaccine programmes due to the wide range of capsular serotypes, of which there are over 90. Current vaccines only provide protection against 7-23 of these, representing the most common clinical serotypes. However, the 23-valent vaccine is unsuitable to give to the most at risk age group of those under two years old, and an increasing amount of serotype replacement is being observed by clinicians whereby non-vaccine serotypes are beginning to replace those included in the vaccine as the cause of disease. Regarding pathogenicity, S. pneumoniae has an array of virulence factors including a highly immunogenic polysaccharide capsule, an extensive number of surface proteins and adhesins, and the toxin pneumolysin. However, the specific role of many virulence factors and their genetic regulation is poorly understood and much remains to be discovered if we are to work towards improved diagnosis, treatment and prevention of pneumococcal disease. The aim of my PhD is to work towards improved understanding of the genetic basis for toxicity in this bacterium, with the specific aim of using a functional genomics approach to identify novel genes associated with the toxic phenotype. Genes which are identified through this approach will then be characterised to elucidate further the complex genetic regulation of this trait. Whilst primarily contributing to improved knowledge and understanding of S. pneumoniae toxicity, this research may also result in identification of novel drug targets for treatment of disease, and it is hoped will contribute to an improved ability to interpret genome sequencing data, which will be useful in a clinical context in the long term. I will achieve these aims by building on the work done in my first year; so far I have assayed the toxicity of a collection of clinical S. pneumoniae isolates of the PMEN1 clonal group and used this data in combination with data regarding the presence of genetic polymorphisms in each isolate to perform a genome wide association study. This has identified a number of genetic loci which are significantly associated with the toxic phenotype, of which we are now working towards identifying the most biologically relevant polymorphisms to investigate further in the lab. This project is BBSRC funded, and fits into the World class underpinning bioscience area of research which encompasses fundamental research in a broad range of areas. My work fits into the discipline of molecular biology, which is one of the high priority research areas of the BBSRC, and it is hoped will contribute to discovery of new leads for drugs or prevention strategies in the context of infectious disease.