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Title: Interference with lysosomal biogenesis by Salmonella typhimurium
Author: McGourty, Kieran D.
ISNI:       0000 0004 2736 9895
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Salmonella enterica is an intracellular bacterial pathogen that replicates within membrane-bound vacuoles by delivering virulence (effector) proteins across the vacuolar membrane by the SPI-2 type III secretion system (T3SS). In this thesis I show that through the action of this T3SS, Salmonella selectively interferes with a subset of endosome-to-trans-Golgi network (TGN) traffic that is involved in mannose-6-phosphate receptor (MPR) recycling. Two pathways of endosome-to-TGN traffic have been described: one involves the Q-SNARE syntaxin 6; the other is defined by the Q-SNARE syntaxin 10 and involves retrograde transport of the MPRs. Salmonella specifically disrupted syntaxin 10-dependent endosome-to- TGN traffic and this was accompanied by redistribution of MPR from the TGN, misrouting of newly synthesized lysosomal enzymes and attenuation of lysosome function. The SPI-2 T3SS effector SifA is an important virulence determinant that is known to interact with the endolysosomal system. SifA was shown to be required and sufficient to mediate the effects on lysosome biogenesis during infection or following transfection of host cells. By contrast, a variant of SifA with a single amino acid substitution that prevents interaction with its host protein target, SKIP, failed to redistribute MPR or to reduce lysosomal function. SKIP was found to contribute to lysosomal biogenesis in uninfected cells. Inhibition of lysosomal enzyme function with a lysosomal protease inhibitor or by depleting cells of syntaxin 10 enhanced intracellular bacterial replication. I conclude that SifA attenuates lysosomal activity through its interaction with SKIP and that this facilitates intracellular bacterial replication.
Supervisor: Holden, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral