EnterohemorrhagicEscherichia colisuppresses inflammatory response to cytokines and its own toxin

Abstract

Infection with the enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes a variety of symptoms ranging from nonbloody diarrhea to more severe sequelae including hemorrhagic colitis, altered sensorium and seizures, and even life-threatening complications, such as hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. The more severe consequences of EHEC infection are attributable to the production of Shiga toxin (Stx) and its subsequent effects on the vasculature, which expresses high levels of the Stx receptor, Gb3. Interestingly, the intestinal epithelium does not express Gb3. Despite the lack of Gb3 receptor expression, intestinal epithelial cells translocate Stx. The effect of Stx on intestinal epithelial cells is controversial with some studies demonstrating induction of inflammation and others not. This may be difficult to resolve because EHEC expresses both proinflammatory molecules, such as flagellin, and factor(s) that dampen the inflammatory response of epithelial cells. The goal of our study was to define the effect of Stx on the inflammatory response of intestinal epithelial cells and to determine whether infection by EHEC modulates this response. Here we show that Stx is a potent inducer of the inflammatory response in intestinal epithelial cells and confirm that EHEC attenuates the induction of IL-8 by host-derived proinflammatory cytokines. More importantly, however, we show that infection with EHEC attenuates the inflammatory response by intestinal epithelial cells to its own toxin. We speculate that the ability of EHEC to dampen epithelial cell inflammatory responses to Stx and cytokines facilitates intestinal colonization.

Host Inflammatory Response Inhibits Escherichia coli O157:H7 Adhesion to Gut Epithelium through Augmentation of Mucin Expression

“…Our results indicated that E. coli O157:H7 attenuated both basal and TNF-␣-induced activation of NF-B p65 signaling in HT-29 cells 3 h postinfection. In contrast to our results, a previous study indicated that EHEC infection enhanced NF-B signaling in T84 cells (24). IL-18 is an important inflammatory cytokine involved in both innate and adaptive immunity.…”

“…This is in agreement with previous studies showing that E. coli O157:H7 infection elevated IL-8 mRNA expression in T84 cells (24,39) and Caco-2 cells (40). In addition, Bellmeyer et al (24) reported that EHEC infection reduced IL-8 production in HT-29 cells in response to TNF-␣ challenge.…”

“…To test the effect of the inflammatory response on E. coli O157:H7 adhesion to epithelial cells, we treated HT-29 cells with TNF-␣, which is known to induce inflammatory cytokine expression (24). As indicated in Fig.…”

Inhibition of NF-κB Signaling in Human Dendritic Cells by the Enteropathogenic Escherichia coli Effector Protein NleE

“…These results support data obtained on rabbit enterocytes (6) and human epithelial cell lines cells (9)(10)(11), which showed a type III secretion dependent reduction of IL-8 production. Similar results were recently reported for EHEC, which can downregulate the proinflammatory cytokine production by intestinal epithelial cells in response to its own Shiga toxin (20) and uses the effector NleH1 to subvert NF-kB-dependent transcription by binding to the ribosomal protein s3 (21).…”

Enteric pathogens and gut function: Role of cytokines and STATs

“…In addition, recent evidence suggests that a number of A/E pathogens, in turn, generate factors that down-regulate the inflammatory response thereby preserving the integrity of epithelial cells that is critical for colonization. 41 These data emphasize the importance of immune-mediated regulation of bacterial and host cell interactions.…”