Grant: Fellowship: Bisby (Prize)

More than a century after Pasteur put forth his microbial theory of disease and decades after the advent of antibiotics,infectious disease remains the second leading cause of death worldwide. Furthermore, susceptibility to infectious agents varies widely among individuals, which can impact therapy and public health management. Disease severity is largely dependent on genetic variation in the host but also influenced by genetic variation in the pathogen. This project aims to identify common variants in the human population that confer susceptibility to the intracellular pathogen, Francisella, the highly infective, causative agent of tularemia. As a potential bio-warfare agent, Francisella represents a unique threat to public health and safety; it also serves as an excellent model to study the pathogenesis of intracellular bacteria. We will use a high throughput screen to assess various cellular phenotypes, including invasion, replication and cell death in cell lines derived from >500 individuals of diverse ethnic backgrounds. With this method, we can examine the association between natural polymorphisms and variation in response to infection without the confounding effects of exposure level, pathogen strain or treatment availability. The identified variant alleles will be characterized at the cellular level, through various RNA interference and over-expression approaches, to probe the mechanistic basis of how host genetic variation influences susceptibility to Francisella. A greater understanding of the cellular host response to infection, with particular emphasis on components of innate immunity and inflammation, will begin to elucidate the host genetic contribution to microbial disease. In addition, examining the natural occurring genetic variants will provide some insight into natural selection by infectious pathogens throughout human evolution and the potential negative impact of such "infection protective" alleles on inflammatory diseases or autoimmunity.