# Shiga Toxin Therapeutics: Beyond Neutralization
## 1 Introduction  
Shiga toxins are ribotoxic proteins produced by several species of bacteria responsible for epidemic outbreaks of human gastrointestinal disease [1; 2]. The prototypical toxin of this group is Shiga toxin produced by _Shigella dysenteriae_ Type 1, an etiologic cause of bacterial dysentery associated with contaminated water supplies [3; 4]. The related proteins Shiga-like toxin 1 (STX1) and Shiga-like toxin 2 (STX2) are produced by various pathogenic strains of Shiga toxin-producing _Escherichia coli_ (STEC) responsible for food-borne illnesses globally, including numerous outbreaks in the United States, Europe, South America, and Japan [5; 6; 7]. STX1 and 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]. Neurologic disease is a frequent complication of STEC infection via imprecisely defined mechanistic causes [13; 12; 14]. Approximately 5-30% of patients suffer long term morbidity from chronic renal insufficiency, hypertension, or neurological deficits following the resolution of active HUS [15]. Children younger than 2 years of age are particularly susceptible to Shiga toxin-induced HUS, and the overall HUS rates vary between 5-15% of confirmed STEC cases depending on the infecting bacterial strain. The recent European outbreak involving an atypical STEC O104:H4 strain showed substantiallyhigher rates of adult HUS in part due to its enteroaggregative properties, and future emerging Shiga toxin-producing pathogens may have variant epidemiological profiles [6; 16; 17]. STEC strains are susceptible to antibiotics, but antibiotic therapy is generally contraindicated due to an association of antibiotic treatment with increased toxin production and risk of HUS development [18; 19]. However, 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. As a result, the standard of care remains supportive and avoids antibiotics. The clinical management of STEC cases is complicated further by the lack of validated clinical biomarkers capable of predicting HUS onset prior to the development of thrombocytopenia and renal damage. There are no commercially approved therapeutics that specifically treat or prevent HUS caused by Shiga toxin-producing pathogens, and supportive care with careful fluid management is the recommended treatment following diagnosis [21]. Plasmapheresis and treatment with the C5 complement inhibitor \(\mathrm{E}\mathrm{c}\mathrm{u}\mathrm{i}\mathrm{z}\mathrm{u}\mathrm{a} \mathrm{a}\mathrm{b}\) have not shown consistent clinical benefits in human patients [22; 23]. Due to the diversity of _E. coli_ serotypes capable of causing Shiga toxin-mediated disease and the potential of new emerging 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. The focus of therapeutic development for Shiga toxicosis and HUS has been the blockade of toxin activity or intracellular trafficking. Thus far, no Shiga toxin-specific therapeutic has advanced past Phase II clinical trials in the United States, partially due to the difficulties in drug development for a sporadic acute disease [24]. In this review, an alternate strategy of therapeutic development is explored that proposes to target the downstream signaling and outcomes of Shiga toxin activity.