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Title: Manipulating cell trafficking by bacterial effector proteins
Author: Furniss, Robert Christopher David
ISNI:       0000 0004 7963 7134
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The enteric pathogens Enteropathogenic and Enterohaemorrhagic Escherichia coli (EPEC/EHEC) subvert a range of fundamental host cell processes to establish infection in the gut lumen and cause disease. This manipulation is achieved through injection of a suite of bacterial effector proteins into infected host cells via a Type 3 Secretion System. However, the precise contribution of many of these effectors to EPEC/EHEC infection remains to be determined. EspG is a highly conserved effector protein, found across EPEC and EHEC strains, and has been shown to have pleiotropic effects in infected cells. Here we report that EspG manipulates host protein trafficking through interaction with the small GTPases ARF6 and Rab35. EspG directly binds GTP-ARF6, which recruits EspG to endosomal structures in EHEC infected cells. EspG subsequently interacts with Rab35 and causes intracellular accumulation of the Transferrin Receptor, an archetypal host recycling cargo. Investigation of other EspG-family members, including the homolog VirA from the intracellular pathogen Shigella flexneri, reveals that EspG is capable of complementing an S.flexneri ∆virA mutant, and that EspG's from different AE pathogens may have altered interactions with ARF6 during infection. Finally, using quantitative cell surface proteomics we reveal that EspG manipulates the cell surface levels of a range of different host proteins and confirm that the recycling population of the cell surface glycoprotein Podocalyxin is reduced at the cell surface in an EspG-dependent manner. These observations may explain the range of seemingly disparate activities previously attributed to EspG and to the best of our knowledge represent the first report of global manipulation of the host cell surface proteome by a bacterial pathogen.
Supervisor: Clements, Abigail Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral