Shigella flexneri is a facultative intracellular bacterium and a paradigm to address key issues in cell biology and cell-autonomous immunity. Cell-autonomous immunity is a system of host defence that senses invading pathogens and mobilises anti-pathogen mechanisms, including autophagy. Recently, it has become clear that the cytoskeleton is directly linked to cell-autonomous immunity. During my PhD, I used S. flexneri to investigate bacterial factors that mediate interactions with the cytoskeleton and cell-autonomous immunity.
Bacteria have counterparts to the host cytoskeleton components actin (e.g. MreB), microtubules (e.g. FtsZ), intermediate filaments (e.g. CreS) and septins (MinCD). However, rearrangements of the bacterial cytoskeleton have never been followed in pathogenic bacteria during infection of host cells. In Chapter 1, I generate new tools to follow the Shigella MreB, FtsZ and MinC cytoskeleton during infection of host cells using fluorescence microscopy.
S. flexneri can exploit the host actin cytoskeleton to form ‘actin tails’ for its own motility. Actin-based motility enables bacterial cell-to-cell spread and evasion of the immune system. Polar localisation of the autotransporter IcsA is required for efficient actin tail formation, yet how IcsA is targeted to the bacterial cell pole was not fully known. In Chapter 2, I use Shigella MreB-msfGFPsw to reveal that MreB targets IcsA to the bacterial cell pole to promote actin tail formation and autophagy escape.
To entrap Shigella for autophagy, the host septin cytoskeleton forms cage-like structures around actin polymerising bacteria. How septins recognise bacteria is poorly understood. In Chapter 3, I report that septins sense micron-scale curvature, cardiolipin and cell growth of dividing bacterial cells to inhibit Shigella cell division via autophagy and lysosome fusion. Therefore, the host septin cytoskeleton offers great potential to boost the recognition and restriction of dividing bacterial cells.
Overall, the findings in this thesis have discovered that by controlling bacterial cell polarity, morphology and division, the bacterial cytoskeleton shapes host-pathogen interactions. Moreover, they highlight that investigation of the bacterial cytoskeleton during infection can inspire the development of new therapeutic regimes for infection control.Open Acces
