## 3 Hemolytic Uremic Syndrome (EHEC and Stx)
Stx induces an inflammatory and chemotactic environment, and recruited neutrophils may transport the toxins in the blood [67], which could explain how the toxin passes from the gut to the kidney without bacteremia or invasion by the EHEC. Whether this occurs in patients is debated [68] because Stx antigen is sometimes [67, 69, 70], but not always [71] detected on the surface of circulating neutrophils. Close proximity of neutrophils and their enzymes to renal endothelial cells can also alter the surface availability of some proteins, changing the functionality of the endothelium. It is well known that neutrophil elastase cleaves endothelial-expressed thrombomodulin [72], a necessary cofactor of the protein C anticoagulant pathway [59]. If this proteolysis is incomplete, and removes only the amino-terminal lectin domain of thrombomodulin, this may contribute to organ injury and thrombotic microangiopathy, as suggested in murine models of Stx2 challenge with endotoxin priming [73]. It is interesting to note that while this information helps to explain the forces driving disease in the kidney and other organs, they do not go as far in explaining the neurological signs that are often seen accompanying HUS. In the recent 2011 German outbreak of EHEC infection, the rate of HUS was unusually high and the neurologic complications were severe, from aphasia to epileptic seizures. Notably, there were no histologically observed brain microthrombi, vessel occlusions or evidence of ischemia [74]. How then did the patients develop neurological symptoms, and was Stx to blame? One study in rats has shown that Stx1 effect on astrocytes could indirectly affect the blood-brain barrier [75]. During the German outbreak, immunoadsorption of IgG helped attenuate the neurological complications of Stx2-producing _E. coli_ O104:H4 [76]. They did not find evidence that the antibodies were directed against ADAMTS13, loss of which contributes to a related thrombotic microangiopathy (see below), and instead hypothesized that the antibodies were against Stx itself and were crosslinking receptors, causing the release of larger von Willebrand Factor multimers [77] to indirectly inhibit ADAMTS13 [65] and increasing risk of thrombus formation. Further investigation will show whether this interesting hypothesis is true. A potential role for the complement pathway during development of Stx-induced HUS has recently gained renewed interest. Complement is an ancient non-specific opsonic defense mechanism dating to pre-Cambrian ancestors [78], and is now a highly regulated mammalian innate immune strategy contributing to host defense or tissue injury depending on the context [79]. There is some evidence that complement is activated during EHEC infection. During acute phase EHEC-HUS, complement factor C3 or C9 is detected on platelet-leukocyte complexes from patients, and Stx can induce _ex vivo_ release of complement-bearing microparticles from platelets or monocytes [80]. Using purified components, Stx2 was shown to activate complement via the alternative pathway and slow complement factor H (CFH) regulatory activity [81]. A recent study showed Stx-induced C3b interactions with P-selectin to promote a pro-thrombotic surface on dermal microvascular endothelial cells activated with human serum and/or blood under shear stress [82]. These observations, along with C3 deposition on glomeruli from mice challenged with Stx2 + LPS [82], suggest a role for complement in the pathophysiology of endothelial dysfunction during HUS. However, patient data has less apparent clarity. In a small patient study, increased levels of alternative pathway members Bb and SC5b-9 were observed early in D + HUS patients, but there was no correlation with clinical parameters or outcome [83]. There also was no comparison with non-EHEC renal patients so it is difficult to evaluate a specific relationship to Stx-HUS as opposed to a generalized host defense response.