Abstract
BackgroundEnteropathogenic (EPEC) and Enteroaggregative (EAEC) E. coli have similar, but distinct clinical symptoms and modes of pathogenesis. Nevertheless when they infect the gastrointestinal tract, it is thought that their flagellin causes IL-8 release leading to neutrophil recruitment and gastroenteritis. However, this may not be the whole story as the effect of bacterial adherence to IEC innate response(s) remains unclear. Therefore, we have characterized which bacterial motifs contribute to the innate epithelial response to EPEC and EAEC, using a range of EPEC and EAEC isogenic mutant strains.MethodologyCaco-2 and HEp-2 cell lines were exposed to prototypical EPEC strain E2348/69 or EAEC strain O42, in addition to a range of isogenic mutant strains. E69 [LPS, non-motile, non-adherent, type three secretion system (TTSS) negative, signalling negative] or O42 [non-motile, non-adherent]. IL-8 and CCL20 protein secretion was measured. Bacterial surface structures were assessed by negative staining Transmission Electron Microscopy. The Fluorescent-actin staining test was carried out to determine bacterial adherence.ResultsPrevious studies have reported a balance between the host pro-inflammatory response and microbial suppression of this response. In our system an overall balance towards the host pro-inflammatory response is seen with the E69 WT and to a greater extent O42 WT, which is in fit with clinical symptoms. On removal of the external EPEC structures flagella, LPS, BFP, EspA and EspC; and EAEC flagella and AAF, the host inflammatory response is reduced. However, removal of E69 lymphostatin increases the host inflammatory response suggesting involvement in the bacterial mediated anti-inflammatory response.ConclusionEpithelial responses were due to combinations of bacterial agonists, with host-bacterial contact a key determinant of these innate responses. Host epithelial recognition was offset by the microbe's ability to down-regulate the inflammatory response. Understanding the complexity of this host-microbial balance will contribute to improved vaccine design for infectious gastroenteritis.
Highlights
Diarrhoeal disease is the second leading cause of infant mortality under the age of 5 worldwide with 1.5 million infant deaths each year, in addition to 1.1 million deaths in adults and infants over the age of 5 [1]
In our system an overall balance towards the host pro-inflammatory response is seen with the E69 wild type (WT) and to a greater extent O42 WT, which is in fit with clinical symptoms
If an inflammatory response ensues, it is due to the host proinflammatory response to enteropathogenic E. coli (EPEC) outweighing the bacterial three secretion system (TTSS) mediated anti-inflammatory response [4]. (III) Intimate adherence via an attaching and effacing (A/E) lesion [5], causing microvillus effacement that results in persistent watery diarrhoea, which ranges from non to weakly inflammatory [6]
Summary
Diarrhoeal disease is the second leading cause of infant mortality under the age of 5 worldwide with 1.5 million infant deaths each year, in addition to 1.1 million deaths in adults and infants over the age of 5 [1]. Common amongst the Diarrhoeagenic Escherichia coli strains is the ability to colonise the intestinal mucosa, evade host defences, multiply and cause host damage. One such strain, enteropathogenic E. coli (EPEC), is a human pathogen of the small intestine and is a significant cause of infantile diarrhoea [2]. Enteropathogenic (EPEC) and Enteroaggregative (EAEC) E. coli have similar, but distinct clinical symptoms and modes of pathogenesis When they infect the gastrointestinal tract, it is thought that their flagellin causes IL-8 release leading to neutrophil recruitment and gastroenteritis. This may not be the whole story as the effect of bacterial adherence to IEC innate response(s) remains unclear. We have characterized which bacterial motifs contribute to the innate epithelial response to EPEC and EAEC, using a range of EPEC and EAEC isogenic mutant strains
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