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Title: The roles of bacterial virulence mechanisms, including intracellular persistence, in determining outcome of infection by invasive nontyphoidal Salmonella
Author: Rycroft, Julian Anthony
ISNI:       0000 0004 6496 2452
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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While typhoidal serovars of Salmonella are human-restricted and cause invasive disease, nontyphoidal serovars infect a range of mammalian hosts, causing enterocolitis or systemically disseminated “invasive” disease. Invasive nontyphoidal salmonellosis is a major neglected tropical disease. In sub-Saharan Africa emergent clades of genetically distinct invasive strains are amongst the most common cause of bacteraemia. Prevalence, mortality and recurrence are all high. There is growing evidence that recurrence is attributable to resuscitation of non-growing intracellular persister Salmonella, the induction of which depends on a repertoire of class II toxin-antitoxin modules. A selection of invasive strains of S. Typhimurium and S. Enteritidis were experimentally compared to non-invasive reference strains with the aim of identifying pathogen factors associated with invasive disease. Invasive strains were less efficient at infecting human epithelial cells cultured in vitro, reflecting the loss of genes associated with an enteric lifestyle from these strains. Invasive strains were also less pro-inflammatory than reference strains, and induced less IL-1β secretion from human macrophage-like cells infected in vitro; although there was no evidence for superior survival of invasive strains within mammalian macrophages. All invasive strains were able to undergo the phenotypic switch to the persister state following internalisation by human macrophages, especially macrophages polarised to the pro-inflammatory, replication-restricting M1 phenotype. Investigating differences in the TA repertoire between serovars facilitated the characterisation of two members of a novel family of three Salmonella class II toxins. These two toxins induced the persister state by inhibiting translation, which was dependent on the transfer of an acetyl moiety to a negatively charged substrate. A genomic screen revealed a potential role for multiple genes in persister resuscitation and added evidence to the assertion that the negatively charged substrate of these toxins, as is already known to be the target of third member TacT, is also aminoacylated-tRNA.
Supervisor: Holden, David ; Maclennan, Calman Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral