Abstract
Enterohemorrhagic Escherichia coli (EHEC) are food-borne pathogens that can cause serious infections ranging from diarrhea to hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS). Translocation of Shiga-toxins (Stx) from the gut lumen to underlying tissues is a decisive step in the development of the infection, but the mechanisms involved remain unclear. Many bacterial pathogens target the follicle-associated epithelium, which overlies Peyer's patches (PPs), cross the intestinal barrier through M cells and are captured by mucosal macrophages. Here, translocation across M cells, as well as survival and proliferation of EHEC strains within THP-1 macrophages were investigated using EHEC O157:H7 reference strains, isogenic mutants, and 15 EHEC strains isolated from HC/HUS patients. We showed for the first time that E. coli O157:H7 strains are able to interact in vivo with murine PPs, to translocate ex vivo through murine ileal mucosa with PPs and across an in vitro human M cell model. EHEC strains are also able to survive and to produce Stx in macrophages, which induce cell apoptosis and Stx release. In conclusion, our results suggest that the uptake of EHEC by M cells and underlying macrophages in the PP may be a critical step in Stx translocation and release in vivo. A new model for EHEC infection in humans is proposed that could help in a fuller understanding of EHEC-associated diseases.
Highlights
Enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC), have been associated with human diseases, ranging from uncomplicated diarrhea to hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS)
Since EHEC O157:H7 was found to interact initially with follicle-associated epithelium (FAE) in both humans and cattle [12,16,24], we hypothesized that the uptake of bacteria by M cells and underlying macrophages may be the first stage in Stx translocation, and may represent an important step in the pathogenesis of EHEC infections
The integrity of ileal mucosa was monitored throughout Ussing chamber experiments: Fluorescein isothiocyanate (FITC) diffusion was limited and there was no difference between Stx-producing bacteria and non pathogenic E. coli (Figure S1)
Summary
Enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC), have been associated with human diseases, ranging from uncomplicated diarrhea to hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS). Several studies have reported a high prevalence of STEC belonging to a wide range of serotypes in animals and food products [3,4,5]. Only a limited number of serotypes have been associated with human disease, among which O157:H7 is predominant [3,6]. The association of serotypes with disease of varying severity in humans and with outbreaks or sporadic disease has led to the proposal that STEC be classified into 5 seropathotypes, from A (most virulent) to E (serotypes that have not been involved in disease in humans) [7]
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