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Title: The septin cage : a novel mechanism of host defence to restrict bacterial replication
Author: Sirianni, Andrea
ISNI:       0000 0004 7657 1539
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Autophagy is a highly conserved intracellular degradation process crucial for cell-autonomous immunity against bacterial infection. However, some bacteria may subvert the host cytoskeleton to escape recognition from autophagy. In the cytosol, Shigella flexneri and Listeria monocytogenes use actin-based motility to avoid cell-autonomous immunity and spread from cell-to-cell. The host cytoskeleton plays a key role in autophagy and its ability to restrict or promote bacterial replication. Septins, a cytoskeletal component that interacts with cellular membranes and actin filaments, are GTP-binding proteins that polymerize into non-polar filaments and rings. Our lab has discovered that septin cage-like structures entrap actin-polymerising Shigella targeted to autophagy. The septin cage is recognized as a mechanism of host defence mechanism, however the precise fate of septin cage entrapped Shigella remains unknown. Evidence has suggested that mitochondria provide membrane for the biogenesis of autophagosomes during starvation. The role of the mitochondria during the autophagy of Shigella is unknown. Mitochondria are highly dynamic organelles characterised by events of membrane fission and fusion. Work has previously established a role for the host cell division machinery, i.e. actin and myosin, in the regulation of mitochondrial dynamics (a process called 'mitokinesis'). Whether septins are also involved in mitochondrial dynamics has not yet been tested. For my thesis, the entrapment of Shigella by septin cages was used as a paradigm to better understand host defence against bacterial infection and to discover new septin biology. Results have shown that mitochondria mediate the assembly of septins into cage that target Shigella to degradation by autophagy. We have also discovered that septins regulate mitochondrial fission. Finally, we have revealed a new link between septins, autophagy, and host cell metabolism. Together these results suggest that a more complete understanding of septin biology during bacterial infection can enable its manipulation for therapeutic purposes.
Supervisor: Mostowy, Serge ; Pelicic, Vladimir Sponsor: Imperial College London ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral