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• infectious disease and the immune system

• Medicine
• Pathology

• Gastroenterology
• Infectious diseases
• Immunology

My lab is interested in unraveling the molecular mechanisms that underpin bacteria-host interactions. One of our research interests focuses on understanding the genetic requirements for the formation of a healthy gut microbiome. To this end we are using 2 important Gram-negative, commensal (i.e. beneficial) bacteria that colonise the human gut as model systems; Escherichia coli and Bacteroides thetaiotamicron. Using a number of recently developed molecular-based approaches (based on next-generation sequencing and high-resolution transposon mutagenesis) we are currently undertaking global screens to identify factors that are important for the establishment of these bacteria in the mammalian gut. It is hoped that these studies will provide a comprehensive genetic framework to facilitate a rationale-based approach towards the development of gut-targeted biotherapeutics that will support improved human health.

Until recently the focus of infectious disease research has been on understanding how pathogens infect new hosts and cause disease. It is only recently that it has become apparent that non-pathogenic and/or beneficial bacteria must also be able to infect their host and, in doing so, support the well-being of that host. Moreover "infecting" a host with non-harmful bacteria can prevent the subsequent infection of the same host with a pathogenic bacterium. For example, pathogenic E. coli are excluded from hosts that have been pre-colonised with particular, non-harmful strains of E. coli (Meador et al (2014) Infect Immun 82:1931-1938). However, a global understanding of the molecular mechanisms that underpin this exclusion are not fully understood. Such an understanding would provide a framework for the development of rationale-based approaches aimed at modulating the gut microbiome in order to prevent acute (i.e. gastroenteritis) and chronic (e.g. Inflammatory Bowel Disease) bacterial pathologies of the gut.

In this project you will construct highly-redundant mutant libraries in selected pathogenic and non-pathogenic strains of E. coli. These libraries will be used to infect animal hosts and, by using next-generation sequencing, we will be able to identify genes that are important for host colonization (see Chao et al (2015) Nature Rev Microbiol 14:119-128 for a recent review of this technology). More importantly, by co-infecting mice with different libraries (derived from pathogenic and non-pathogenic strains) we will be able identify genes that are important for the competitive colonization of an animal host. The role of these genes will be further studied using molecular and biochemical approaches that are well-established in the host laboratory. In this way novel gene targets will be identified for the development of biotherapeutics (e.g. ?designer? bacterial strains) that will modulate the activity of the microbiome in a controlled and predictable manner.