Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Toxins (Basel). 2017 Sep 19;9(9):291. doi: 10.3390/toxins9090291.
Ribotoxic Shiga toxins are the primary cause of hemolytic uremic syndrome (HUS) in patients infected with Shiga toxin-producing enterohemorrhagic (STEC), a pathogen class responsible for epidemic outbreaks of gastrointestinal disease around the globe. HUS is a leading cause of pediatric renal failure in otherwise healthy children, resulting in a mortality rate of 10% and a chronic morbidity rate near 25%. There are currently no available therapeutics to prevent or treat HUS in STEC patients despite decades of work elucidating the mechanisms of Shiga toxicity in sensitive cells. The preclinical development of toxin-targeted HUS therapies has been hindered by the sporadic, geographically dispersed nature of STEC outbreaks with HUS cases and the limited financial incentive for the commercial development of therapies for an acute disease with an inconsistent patient population. The following review considers potential therapeutic targeting of the downstream cellular impacts of Shiga toxicity, which include the unfolded protein response (UPR) and the ribotoxic stress response (RSR). Outcomes of the UPR and RSR are relevant to other diseases with large global incidence and prevalence rates, thus reducing barriers to the development of commercial drugs that could improve STEC and HUS patient outcomes.
核糖体毒性志贺毒素是产志贺毒素肠出血性大肠杆菌（STEC）感染患者溶血性尿毒症综合征（HUS）的主要原因，该病原体类别负责在全球范围内引发胃肠道疾病的流行爆发。HUS 是 otherwise healthy children 中儿童肾衰竭的主要原因，导致死亡率为 10%，慢性发病率接近 25%。尽管数十年来一直在阐明敏感细胞中志贺毒素毒性的机制，但目前仍没有针对 STEC 患者的预防或治疗 HUS 的治疗方法。尽管存在零星的、地理上分散的 STEC 爆发和 HUS 病例，但由于急性疾病的患者人群不一致，商业开发治疗方法的经济激励有限，毒素靶向 HUS 治疗的临床前开发受到阻碍。以下综述考虑了针对 Shiga 毒性下游细胞影响的潜在治疗靶向，包括未折叠蛋白反应（UPR）和核糖体毒性应激反应（RSR）。UPR 和 RSR 的结果与其他具有高全球发病率和患病率的疾病相关，从而降低了开发可改善 STEC 和 HUS 患者预后的商业药物的障碍。
