The role of Shiga toxin in promoting transepithelial migration of neutrophils

Abstract

The Shiga toxin (Stx)‐producing E. coli are human pathogens of significant importance. Among these bacteria, enterohemorrhagic E. coli (EHEC) have been most frequently associated with outbreaks of foodborne illness, causing hemorrhagic colitis that can lead to severe systemic disease. Recently, a major outbreak in Germany was caused by an enteroaggregative E. coli (EAEC) strain that had acquired the Stx genes. Clinical data from patients suggest that inflammatory responses may play an important role during both EHEC and EAEC disease. Here, we show that EHEC induces transepithelial migration of neutrophils (PMNs) across polarized colonic epithelial cells. Furthermore, deletion of the Stxencoding genes significantly attenuates this inflammatory event. Stx has been implicated in other inflammatory pathways, including up‐regulation of pro‐inflammatory cytokines in intestinal cells via activation of the ribotoxic stress response (RSR). We have found that inhibition of ZAK, a host cell kinase that is required to initiate the Stx‐induced RSR, inhibits the ability of EHEC to induce PMN transepithelial migration, similar to the effects of Stx deletion. We conclude that Stx‐mediated activation of the RSR likely plays a key role in EHEC‐induced PMN transepithelial migration. Further research will examine whether Stx plays a similar role in inducing inflammatory PMN migration to the German outbreak strain.