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Title: Regulation of host tyrosine kinases by the Escherichia coli and Salmonella ADP-ribosyltransferases EspJ, SeoC and SboC
Author: Pollard, Dominic James
ISNI:       0000 0004 7427 7563
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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The human pathogens enteropathogenic and enterohaemorrhagic E. coli (EPEC and EHEC) and Salmonella enterica are responsible for a significant proportion of the global diarrhoeal disease burden. EPEC, EHEC and the mouse restricted pathogen C. rodentium (CR) make up the attaching and effacing (A/E) pathogens. CR is used to model EPEC/EHEC pathogenesis in vivo, where it colonises the apical surface of mouse intestinal mucosae, destroying microvilli and inducing colonic crypt hyperplasia (CCH) and diarrhoeal disease symptoms. The type three secretion system (T3SS) is instrumental to the infectivity of the A/E pathogens, as well as Salmonella, through the injection of sets of effector proteins into the host cell cytosol for the manipulation of host cell signalling. Prior to this study the A/E pathogens T3SS effector EspJ was identified as a novel enzyme that can disrupt FcγR and C3R mediated phagocytosis, dependent upon a functional ADP ribosyltransferase (ART) domain. In vitro EspJ was shown to inhibit Src kinase through simultaneous amidation and ADP ribosylation of a conserved kinase domain residue, E310. This study shows that the inhibition of phagocytosis is conserved by the EspJ homologues Salmonella enterica subsp. salamae and arizonae SeoC, S. bongori SboC and Y. enterocolitica YspJ. SeoC is secreted by the Salmonella pathogenicity island (SPI) 1 T3SS but does not impact Salmonella entry into host cells. An in vitro proteomics assay showed that EspJEHEC could ADP ribosylate a multitude of host non receptor tyrosine kinases (NRTK), including Src and its inhibitor Csk which were also ADP ribosylated by SeoC and SboC, but not YspJ. Finally, a proteomics comparison of IECs purified from mice infected with CR expressing functional or non functional EspJ, suggested that EspJ modulates host inflammation and the immune system in vivo.
Supervisor: Frankel, Gad Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral