Abstract
Ribotoxic Shiga toxins are the primary cause of hemolytic uremic syndrome (HUS) in patients infected with Shiga toxin-producing enterohemorrhagic Escherichia coli (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.
Highlights
Shiga toxins are ribotoxic proteins produced by several species of bacteria responsible for epidemic outbreaks of human gastrointestinal disease [1,2]
Shiga-like toxin 1 (STX1) and Shiga-like toxin 2 (STX2) are encoded within the genome of lysogenized bacteriophages that can be transferred between related bacteria, creating a diverse array of bacterial strains secreting one or more toxin subtypes [1,8]
Shiga toxins are the etiologic cause of post-diarrheal hemolytic uremic syndrome (HUS), a thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure following a course of bacterially induced hemorrhagic diarrhea [9,10,11,12]
Summary
Shiga toxins are ribotoxic proteins produced by several species of bacteria responsible for epidemic outbreaks of human gastrointestinal disease [1,2]. Antibiotic treatment appeared to be effective during the European O104:H4 outbreak, and this was later confirmed by in vitro evaluation of patient isolates [20] This highlights a need for rapid and specific clinical laboratory serotyping coupled with toxin detection, a technology that is not yet available commercially. There are no commercially approved therapeutics that treat or prevent HUS caused by Shiga toxin-producing pathogens, and supportive care with careful fluid management is the recommended treatment following diagnosis [21]. Shiga toxin-producing pathogens, treatments that target the activity of the toxin are currently being sought to prevent the development of HUS and to improve HUS patient outcomes. Shiga toxin-induced stress pathways with common diseases may lead to a more rapid development and approval of commercially available therapeutics to improve patient outcomes compared to the direct targeting of the toxin itself
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