Septins: from bacterial entrapment to cellular immunity

ongoing

The intracellular bacterium Shigella flexneri is an exceptional model pathogen to address key issues in biology, including how bacteria can move inside host cells and escape the immune system. The cytoskeleton has recently emerged to occupy a central role in innate immunity by promoting bacterial sensing and executing antibacterial functions. I discovered that host cells employ septins, a poorly understood component of the cytoskeleton, to restrict the actin-based motility of Shigella and target them for destruction by autophagy, an important mechanism of innate immune defence. However, the processes underlying septin cage assembly, and the breadth of roles for septins in bacterial infection control, remain to be established. I developed zebrafish (Danio rerio) infection models to study the cell biology of Shigella infection in vivo, and to discover new roles for septins in host defence against bacterial infection. This approach has enabled a cutting edge platform for in vivo studies both at the single cell and whole animal level, and provides unprecedented opportunities to follow cytoskeleton dynamics and innate immunity at a resolution that cannot be achieved using any other animal model. I will now exploit the novelty of septin biology, and its direct link to host defence, as the foundation for this research programme. Using Shigella I will: (1) Discover new roles for the cytoskeleton in host defence against bacterial infection, and (2) Investigate the role of septin-mediated host defence mechanisms in vivo using zebrafish models of infection. The results generated from this research programme will provide fundamental advances in understanding septin biology and cellular immunity. They could also suggest the development of new strategies aimed at combating infectious diseases, and possibly other human diseases in which septins have been implicated including neoplasia and neurodegenerative conditions.