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Title: The role of EspO1 in Escherichia coli pathogenesis
Author: Lekmeechai, Sujinna
ISNI:       0000 0004 7228 8090
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Enterohaemorrhagic E. coli (EHEC) has been the causative agent of diarrhoeal outbreaks for decades. EHEC virulence relies on a type 3 secretion system (T3SS), which directly translocates T3SS effectors into the host cell cytoplasm. Once translocated, T3SS effectors alter various host cell functions, including manipulating the cell death response, in order to facilitate bacterial colonisation. EHEC is equipped with at least 40 effector proteins; however, not all identified effectors are fully characterised. This study set out to investigate the role of EspO during EHEC infection. EHEC O157:H7 strain EDL933 carries 2 EspO homologs: EspO1 and EspO2. EspO homologs are also found in several enteric pathogens including Shigella flexneri (OspE1 and OspE2), Salmonella enterica serovar Typhi and Typhimurium (SopD), Citrobacter rodentium (EspO), and some enteropathogenic E. coli (EPEC) clinical isolates (EspO). It has previously been established that the EspO effector family interacts with integrin linked kinase (ILK) via a conserved tryptophan residue: W68 for OspE1 and W77 for EspO1. EspO1 and EspO2 co-operatively inhibit cell detachment by blocking focal adhesion disassembly, via their interactions with ILK and EspM2, respectively. In a previous study, HAX-1 was identified as the novel interaction partner of EspO1 by a yeast 2 hybrid (Y2H) screen. HAX-1 is an ubiquitiously expressed anti-apoptotic protein that localises to mitochondria. In this study, the EspO1-HAX-1 interaction was confirmed by direct Y2H. Functionally, EspO1 and OspE1 were shown to protect HeLa cells from staurosporine-induced apoptosis during transfection and EspO1 was able to inhibit cell death during in vitro infection. Additionally it was established that the EspO1 and OspE1 anti-apoptotic activity is HAX-1 dependent, but ILK independent. To summarise, this study reported that EspO1 displays anti-apoptotic activity in a HAX-1 dependent manner. Therefore, EspO1 serves 2 main functions: inhibition of apoptosis through HAX-1 and blocking of cell detachment through ILK.
Supervisor: Frankel, Gad ; Clements, Abigail Sponsor: Government of Thailand
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral