Analysis of the pathogenic mechanism of Shiga toxin-producing Escherichia coli infection for vaccine development

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Shiga toxin (Stx)-producing Escherichia coli O157 : H7 infection in mice with protein-calorie-malnutrition leads to acute encephalopathy ; thereby, infected animals died within 10-12 days after infection. In infected mice, serum levels of TNF-α was increased 2 days after infection, 1 or 2 days after which Stx was detectable in the blood. Serum levels of IL-10 were also increased after day 5 of infection. In vitro studies, TNF-α accelerated the uptake of Stx by human umbilical venous endothelial cells (HUVEC) as well as the intracellular activation of Stx, which results in apoptosis in HUVEC. Such apoptosis induction was significantly enhanced by first exposing the cells to TNF-α for 6 h and subsequently by incubating them with Stx. IL-10 reduced the apoptosis induced by TNF-α and Stx. These results suggest that Stx damages vascular endothelial cells exposed to circulating TNF-α, thereby entering the brain through the damaged blood-brain barrier, and also that serum IL-10 may protect apoptosis in vascular endothelial cells.