# Protection against Shiga Toxins
## 1 Introduction  
Shiga toxins (Stxs) comprise a family of related bacterial protein toxins that are similar in structure and mechanism of action, but are produced by different types of bacteria. Shiga toxin is secreted by _Shigella dysenteriae_, whereas Shiga-like toxin 1 (Stx1) and Shiga-like toxin 2 (Stx2) are produced by certain strains of _Escherichia coli_ (Shiga toxin-producing _E. coli_ (STEC)) and some other bacteria [1]. Prototypic Stx1 (Stx1a) differs from Shiga toxin only in one amino acid residue in the catalytic A-moiety of the toxin, whereas Stx2 shares only \(\sim\)60% sequence similarity with Shiga toxin and defines an immunologically distinct subgroup comprised of at least seven subtypes of Stx2 [2]. Stx2 is more lethal than Stx1 in animal models [3; 4] and is thought to be the main cause of life-threatening infections in humans. Some STEC produce only one toxin type, either Stx1 or Stx2, while others express a combination of both types and different subtypes [5]. For simplicity, we will use the abbreviation Stx to refer to the whole family of Shiga toxins when discussing general facts about the toxin and/or where the exact type or variant is not known. Infection with enterohemorrhagic STEC may cause hemorrhagic colitis, hemolytic uremic syndrome (HUS), and death [6]. There is no approved treatment of STEC-induced HUS, and the use of antibiotics may worsen the disease by increasing toxin formation and release by the bacteria [7]. In general, HUS occurs in 5%-15% of cases with STEC infection, with children having the highest risk [8], although the large outbreak with a Stx2a-producing enteroaggregative STEC strain in Northern Europe in 2011 demonstrated that there are bacterium-toxin combinations that can be as dangerous to adults as to children [9]. HUS will most often occur 5-13 days after the onset of diarrhea, with amortality of 3%-5% [10; 11]. In addition to direct renal damage, neurological complications may also occur in HUS patients and are important determinants of severity of the condition and mortality rate [12; 13; 14; 15]. Neurological symptoms may be caused by fatigue, cerebral microvascular thrombi, ischemia-hypoxia, or the direct neuronal effects of Stxs [12; 14; 16]. One of the first specific therapeutic approaches against infections with Stxs was the idea of sequestering the toxin once it is released in the gut. In this regard, a novel agent composed of silicon dioxide particles covalently linked to the trisaccharide moiety of the globotriaosylceramide molecule that mediates Stx binding (Synsorb(r) Pk, Synsorb Biotech) was developed. However, although Synsorb(r) Pk was shown to bind and neutralize Stx1 (and Stx2, but less efficiently) in vitro [17], it failed to improve the clinical course of diarrhea-associated HUS in pediatric patients when tested in a randomized clinical trial [18]. The main drawback of neutralization of Stxs in the intestine for the prevention of HUS is that only trace amounts of the toxin reaching circulation are sufficient to induce HUS, and thus a more systemic treatment is required. Taking this into account, analogues of the globotriaosylceramide (Gb3) receptor and Stx antibodies for systematic administration have been developed and proven promising in in vivo models [19; 20; 21]. In addition, human serum amyloid component P (HuSAP) has been found to neutralize Stx2, but not Stx1, in vitro [22], and to protect mice against a lethal dose of Stx2 [23]. Moreover, culizumab, an antibody directed against the complement protein C5, was used in patients with HUS during the outbreak in Northern Europe in 2011 [24] in order to counteract the activation of complement by the toxin [25]. These novel strategies based on direct neutralization of Stx in the intestine and/or circulation and the inhibition of complement have been well described in a recent review by [PERSON] and [PERSON] [26] and thus are not further discussed here.