Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA.
Pediatr Nephrol. 2011 Nov;26(11):2031-9. doi: 10.1007/s00467-011-1913-y. Epub 2011 May 21.
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.
肠出血性大肠埃希菌感染产生的志贺毒素（Stx）是美国健康儿童发生溶血性尿毒症综合征和急性肾损伤的主要原因。抗生素是禁忌的，治疗的重点是针对导致肾脏损伤的细菌毒素的细胞内作用的药物。我们的目的是评估静脉内给予一种与 Stx2 结合的细胞通透性肽（TVP）是否会降低疾病严重程度并使幼年狒狒免受致死剂量的 Stx2（50ng/kg）的影响。TVP（5mg/kg）在给予毒素时（预防方案）或在给予毒素 6 或 24 小时后（每日 1mg/kg 补充直至第 4 天）通过静脉内给予（挽救方案）。在 28 天内监测血液和尿液中的生物标志物。TVP 治疗导致急性肾损伤和正常尿量的临床体征缺失（预防），或在挽救幸存者中监测 28 天时，BUN 和肌酐水平延迟和降低，同时存活。延迟给予肽可显著减少血小板减少症，但令人惊讶的是，即使在挽救幸存者中监测 28 天，也不会改变贫血。这是第一个在动物模型中对抗 Stx2 致死性的成功细胞通透性治疗方法，该方法重现了许多人类对肠内感染的反应。
