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Title: Characterisation of the molecular basis underlying Chlamydial subversion of focal adhesion signaling
Author: Thwaites, Tristan
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Chlamydiae are obligate intracellular bacterial pathogens with medical and veterinary importance. Their principal virulence mechanism is their ability to invade different cell types both in vivo and in vitro. Whilst the human species, Chlamydia trachomatis and Chlamydia pneumoniea, are limited to infection of mucosal epithelium, the veterinary species of Chlamydia caviae, Chlamydia psittaci, Chlamydia abortus, amongst others, tend to establish a more systemic infection causing organ failure, reproductive defects, and spontaneous abortion. The cell invasion mechanism of Chlamydia trachomatis is the best studied, implicating the chlamydial protein TarP and, specifically, the N-terminal domain that is phosphorylated by the Src-family of non-receptor tyrosine kinases. The veterinary species also possess their respective TarP homologues, but they differ from the Chlamydia trachomatis version by lacking the N-terminal phosphodomain. To resolve this issue, and begin to elucidate the alternative invasion mechanism exhibited by the non-trachomatis species, a bioinformatics-based search of potential signalling motif within the highly conserved C-terminal half of TarP was performed. A candidate Vinculin Binding Domain (VBD) and Focal Adhesion Kinase (FAK)-binding motif (LD) were indentified, which were determined to function in recruiting vinculin and FAK to the sites of invasion, respectively. In addition, the VBD positively influenced the actin-recruiting function of the LD motif. Structural modelling revealed the formation of the hydrophobic interface in VBD/vinculin or LD/FAK interaction. Finally, knockout mouse embryonic fibroblasts confirmed a role for vinculin and FAK in invasion. Altogether, the data indicate that TarP-mediated exploitation of focal adhesion signalling represents a pan-chlamydial invasion mechanism. Interestingly, this signalling mechanism was found to have a post-invasion function. Chlamydia infection led to changes in focal adhesions and adherens junctions, which may be important in apoptosis resistance, counteracting the exfoliation cues provided by neighbouring cells, or cell motility and dissemination of infection within the host.
Supervisor: Carabeo, Rey ; Filloux, Alain Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral