Rescue from lethal Shiga toxin 2-induced renal failure with a cell-permeable peptide
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Intestinal infection with Shiga toxin (Stx)-producing E.coli is a leading cause of hemolytic uremic syndrome and acute renal injury in otherwise healthy children in the US. Antibiotics are contraindicated and a therapeutic priority is agents that act intracellularly against the bacterial toxins that drive kidney injury. Our aim was to evaluate whether intravenous administration of a cell-permeable peptide (TVP) that binds to Stx2 will reduce disease severity and rescue juvenile baboons from a lethal Stx2 dose (50 ng/kg). TVP (5 mg/kg) was delivered i.v. simultaneously with toxin (prevention protocol) or at 6 or 24 h after toxin with daily 1 mg/kg supplements up to day 4 (rescue protocols). Biomarkers were monitored in blood and urine up to 28 days. TVP therapy resulted in either absence of clinical signs of acute kidney injury and normal urine output (prevention), or delayed and reduced BUN and creatinine levels (rescue) with concomitant survival. Delayed peptide administration significantly reduced thrombocytopenia, but surprisingly did not alter anemia even when monitored for 28 days in rescued survivors. This is the first successful cell-permeable therapeutic that counteracts Stx2 lethality in an animal model, which recapitulates many of the human responses to enteric infection.
KeywordsShiga toxins Enterohemorrhagic E.coli Hemolytic uremic syndrome Nonhuman primate Acute renal injury
This work was supported by NIH/NIAID U01AI075386 (S.K.). Baboons were purchased from the Oklahoma Baboon Research Resource at the University of Oklahoma Health Sciences Center supported by NIH P40RR012317 (Gary White, Director).
We gratefully acknowledge Drs. Gary White, Roman Wolf (Comparative Medicine), and Gary Kinasewitz (Pulmonary and Critical Care Medicine) at the University of Oklahoma Health Sciences Center for veterinary support and discussions. We thank Danielle Day for technical support and Lyndianne Joseph for administrative assistance.
Disclosure of conflicts of interest
The authors declare they have no conflict of interest.
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