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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Alqasim, AS (2015)
Languages: English
Types: Doctoral thesis
Subjects:
Extraintestinal pathogenic E. coli (ExPEC) is the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing E. coli ST131 clone represents a major challenge to public health worldwide because of its ability to cause a wide range of difficult-to-treat infections in the healthcare and community settings. The key aim of this study was to characterise the traits that give E. coli ST131 a competitive fitness advantage over other potential ExPEC clones. Comparative phenotypic characterisation of a collection of ExPEC strains showed that there was no difference between ST131 and non-ST131 strains in terms of their growth rates in different culture media, their capacity to associate with, invade and form intracellular bacterial communities within T24 human bladder epithelial cells and their ability to persist within U937 human macrophages. Afterwards, this study tested and compared the metabolic activity of a collection of ST131 and non-ST131 strains using two different testing methodologies: API strips and phenotypic microarray (PM) technology. Our API data showed that ST131 strains had a lower metabolic activity for 5 substrates. Further testing of the metabolic activity of E. coli using phenotypic microarray demonstrated the absence of a specific metabolic profile for ST131 strains suggesting that ST131 is not a metabolically distinct lineage of ExPEC and thus altered metabolism might not contribute to the fitness of this clone. The gene content of a group of E. coli including ST131 and non-ST131 strains was investigated to identify the presence of other loci that are uniquely associated with ST131 H30Rx clade, which involves ST131 isolates belonging to the fimH30 lineage and associated with fluoroquinolones resistance and CTX-M-15 production. Our data identified the presence of 150 loci unique to ST131 H30Rx strains, and the most striking finding at a genomic level was the identification of the secondary flagellar locus Flag 2 as a region uniquely associated with ST131 H30Rx strains. The ability of a collection of ST131 and non-ST131 strains to resist human serum was tested and compared. Our data showed that all ST131 and ST73 strains were associated with high serum resistance phenotype, and this might suggest serum resistance as an important factor in driving the current success of this ST131 as a major cause of bloodstream infections worldwide. Given many reports showing that polysaccharide capsules might be a major factor allowing E. coli to resist the human serum, and based on many studies demonstrating the genetic and biochemical diversity in the capsule region of ST131 strains, the capsule region of a collection of ExPEC belonging to ST131 H30Rx clade and non-ST131 was tested in more detail at a genomic and biochemical level. Our capsule genetics data showed a surprising level of diversity within the capsule locus of the H30Rx clade with a phylogenetic distribution highly suggestive of frequent recombination at the locus. Subsequent analysis demonstrated that this recombination had no obvious detectable effect on virulence-associated phenotypes in-vitro. Given the level of diversity observed at the capsule locus of ST131 H30Rx strains, it is tempting to speculate that there is significant selective pressure occurring at this site during the life cycle of the H30Rx clade, and that frequent recombination allows the clade to subvert that pressure and might provide a fitness advantage to ST131. This study provided detailed insights into the phenotypic, metabolic and genetic traits of ST131 and highlighted the factors that might drive its success.

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