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Title: Salmonella Paratyphi A : an insight into mechanisms of typhoidal Salmonella pathogenesis
Author: Mylona, Elli Effrosyni
ISNI:       0000 0004 9357 036X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2020
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The human-restricted, typhoidal Salmonella Paratyphi A (S. Paratyphi A) and S. Typhi are the major causes of enteric (typhoid) fever and are endemic in regions with poor sanitation. Despite the recent increased rate of S. Paratyphi A isolation from patients in Asia, its pathogenesis remains largely unknown. Asymptomatic chronic carriage in the gallbladder is encountered in about 5% of patients and is facilitated by efficient immune evasion. In this study, we have shown that bile changes the expression of > 5% of genes in S. Paratyphi A, including both bile tolerance and virulence-associated genes. S. Paratyphi A and S. Typhi may differentially regulate certain metabolic pathways in response to bile. Furthermore, a clinical S. Paratyphi A isolate appears to exhibit distinct regulatory mechanisms. As inflammasomes have been shown to play a key role in Salmonella infection, we also investigated their role following infection of macrophages with S. Paratyphi A, using S. Typhi and S. Typhimurium as controls. This work demonstrates that S. Paratyphi A and S. Typhi induce pyroptosis, which is lower than that triggered by S. Typhimurium. While the pathway activated during S. Typhi infection remains unclear, S. Paratyphi A-triggered pyroptosis occurs via activation of caspase-1, caspase-4, caspase-8 and NLRP3. Both S. Paratyphi A and S. Typhi require their SPI-1 injectisome to enable inflammasome activation. However, while the Vi antigen of S. Typhi is dispensable for limiting pyroptosis, the S. Paratyphi A FepE-mediated synthesis of very long O-antigen chains impairs macrophage cell death and a ΔfepE mutant elicited enhanced inflammasome activation. Very long O-antigen chains can also act as an inflammasome dampening mechanism in S. Typhimurium, but reduced fepE expression indicates that this strategy is not exploited by this pathogen. Therefore, this work points towards distinct mechanisms of virulence by S. Paratyphi A, highlighting the need for a systematic characterisation of its molecular pathogenesis.
Supervisor: Frankel, Gad Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral