Abstract
Enterohemorrhagic Escherichia coli produce ribotoxic Shiga toxins (Stx), which are responsible for kidney injury and development of hemolytic uremic syndrome. The endoplasmic reticulum (ER) stress response is hypothesized to induce apoptosis contributing to organ injury; however, this process has been described only in vitro. ER stress marker transcripts of spliced XBP1 (1.78-fold), HSP40 (4.45-fold) and CHOP (7.69-fold) were up-regulated early in kidneys of Stx2 challenged mice compared to saline controls. Anti-apoptotic Bcl2 decreased (−2.41-fold vs. saline) and pro-apoptotic DR5 increased (6.38-fold vs. saline) at later time points. Cytoprotective activated protein C (APC) reduced early CHOP expression (−3.3-fold vs. untreated), increased later Bcl2 expression (5.8-fold vs. untreated), and had early effects on survival but did not alter DR5 expression. Changes in kidney ER stress and apoptotic marker transcripts were observed in Stx2-producing C. rodentium challenged mice compared to mice infected with a non-toxigenic control strain. CHOP (4.14-fold) and DR5 (2.81-fold) were increased and Bcl2 (−1.65-fold) was decreased. APC reduced CHOP expression and increased Bcl2 expression, but did not alter mortality. These data indicate that Stx2 induces renal ER stress and apoptosis in murine models of Stx2-induced kidney injury, but decreasing these processes alone was not sufficient to alter survival outcome.
Highlights
Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC) are a significant cause of food-borne illness in the United States [1]
These data demonstrate that renal transcriptional changes consistent with kidney injury occur in Stx2 challenged mice beginning at Day 3 post challenge continuing through euthanasia
The studies presented show, for the first time, that Stx2 induced lethal kidney injury in vivo is accompanied by renal transcriptional changes in endoplasmic reticulum (ER) stress and apoptotic markers
Summary
Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC) are a significant cause of food-borne illness in the United States [1]. When the first U.S outbreak of the EHEC strain O157:H7 was described in 1982, it was considered a rare pathogen [2], but is an annual public health problem and data from recent outbreaks suggests that more virulent strains have emerged [3]. Infections tend to be seasonal, occurring from May to November, and the majority are due to contaminated ground beef or fresh produce [4]. E. coli O157:H7 is the most common infecting strain and has an infectious dose of. Infection presents as a prodromal hemorrhagic colitis [6], and the likelihood that complications will develop is increased in children younger than five years old [7].
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