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Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx)-producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the world. STEC strains expressing Stx type 2 (Stx2) are responsible for the most severe cases of this pathology. Subtilase cytotoxin (SubAB) is another STEC virulence factor that may contribute to HUS pathogenesis. To date, neither a licensed vaccine nor effective therapy for HUS is available for humans. Considering that Ouabain (OUA) may prevent the apoptosis process, in this study we evaluated if OUA is able to avoid the damage caused by Stx2 and SubAB on human glomerular endothelial cells (HGEC) and the human proximal tubule epithelial cell (HK-2) line. HGEC and HK-2 were pretreated with OUA and then incubated with the toxins. OUA protected the HGEC viability from Stx2 and SubAB cytotoxic effects, and also prevented the HK-2 viability from Stx2 effects. The protective action of OUA on HGEC and HK-2 was associated with a decrease in apoptosis and an increase in cell proliferation. Our data provide evidence that OUA could be considered as a therapeutic strategy to avoid the renal damage that precedes HUS. [ABSTRACT FROM AUTHOR]

Background and Purpose Infections with a strain of Escherichia coli producing Shiga toxins could be one of the causes of fetal morbidity and mortality in pregnant women. We have previously reported that Shiga toxin type 2 ( Stx2) induces preterm delivery in pregnant rats. In this study, we evaluate the role of TNF-α, PGs and NO in the Stx2-induced preterm delivery. Experimental Approach Pregnant rats were treated with Stx2 (0.7 ng g−1) and killed at different times after treatment. Placenta and decidua were used to analyse NOS activity by the conversion of L-[14C]arginine into L-[14C]citrulline, levels of PGE2 and PGF2α assessed by radioimmunoassay, and cyclooxygenase ( COX) proteins by Western blot. TNF-α level was analysed in serum by ELISA and by cytotoxicity in L929 cells. The inhibitor of inducible NOS, aminoguanidine, the COX-2 inhibitor, meloxicam, and the competitive inhibitor of TNF-α, etanercept, were used alone or combined to inhibit NO, PGs and TNF-α production respectively, to prevent Stx2-induced preterm delivery. Key Results Stx2 increased placental PGE2 and decidual PGF2α levels as well as COX-2 expression in both tissues. Aminoguanidine and meloxicam delayed the preterm delivery time but did not prevent it. Etanercept blocked the TNF-α increase after Stx2 treatment and reduced the preterm delivery by approximately 30%. The combined action of aminoguanidine and etanercept prevented Stx2-induced preterm delivery by roughly 70%. Conclusion and Implications Our results demonstrate that the increased TNF-α and NO induced by Stx2 were the predominant factors responsible for preterm delivery in rats. [ABSTRACT FROM AUTHOR]

Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor method of prevention for the deleterious effects caused by Stx intoxication. Antibodies are well recognized as affinity components of therapeutic drugs; thus, a previously obtained recombinant human FabC11:Stx2 fragment was used to neutralize Stx2 in vitro in a Vero cell viability assay. Herein, we demonstrated that this fragment neutralized, in a dose-dependent manner, the cytotoxic effects of Stx2 on human glomerular endothelial cells, on human proximal tubular epithelial cells, and prevented the morphological alterations induced by Stx2. FabC11:Stx2 protected mice from a lethal dose of Stx2 by toxin-antibody pre-incubation. Altogether, our results show the ability of a new encouraging molecule to prevent Stx-intoxication symptoms during STEC infection. [ABSTRACT FROM AUTHOR]

Gastrointestinal infection with Shiga toxin-producing Escherichia coli (STEC) causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS), characterized by hemolytic anemia, thrombocytopenia and acute renal failure. The main virulence factor of STEC is Shiga toxin (Stx), which is responsible for HUS development. STEC can produce Stx type 1 and/or 2 (Stx1, Stx2) and their variants, Stx2 being more frequently associated with severe cases of HUS. This pathology occurs in 5–15% of cases with STEC infection when Stx gain access to the bloodstream and causes damage in the target organs such as the kidney and brain. STEC infections affect mainly young children, although the large HUS outbreak with a new Stx2-producing STEC O104:H4 in Europe in 2011 involved more adults than children, and women were over-represented. Maternal infections during pregnancy are associated with adverse pregnancy outcomes. Studies in rats showed that Stx2 binds to the utero-placental unit and causes adverse pregnancy outcomes. In this article, we provide a brief overview of Stx2 action on placental tissues and discuss whether they might cause pregnancy loss or preterm birth. [ABSTRACT FROM AUTHOR]