Role of Complement in Enterohemorrhagic Escherichia coli–Induced Hemolytic Uremic Syndrome

Abstract

Hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in childhood, is mainly caused by infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC). Besides its cytotoxic activity, Stx has been shown to interact with the complement system. Complement breakdown products have been found in serum of HUS patients suggesting complement activation and in vitro studies have demonstrated that Stx2 directly activates complement leading to formation of terminal complement complex. Furthermore, Stx2 has been found to bind to factor H (FH) resulting in a reduced cofactor activity on the cell surface. Binding of Stx2 has also been shown for other members of the FH family, namely FH-like protein 1 and FH-related protein 1. Both proteins also compete with FH for Stx binding, so that in the presence of FHR-1 less FH is bound to Stx and therefore more is available for endothelial cell protection. In addition, Stx2 has been demonstrated to downregulate the membrane-bound regulator CD59 on the surface of glomerular endothelial and tubulus epithelial cells on protein and at the mRNA level. In conclusion, Stx modulates complement regulator proteins leading to an impaired control and thus to enhanced complement activation. Its implication in the pathogenesis of EHEC-induced HUS in vivo and whether complement blockage might be a therapeutic option still has to be elucidated.

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

“…Even though individual patients can respond rapidly with efficient recovery, in larger cohorts of STEC-HUS patients, no significant differences have been seen on mortality or morbidity with the use of eculizumab [47–50]. …”

A Topographical Atlas of Shiga Toxin 2e Receptor Distribution in the Tissues of Weaned Piglets

“…In humans, subtypes Stx2a and Stx1a are the most prominent virulence factors of STEC isolates being responsible for severe gastrointestinal diseases and extraintestinal complications, including hemorrhagic colitis and hemolytic uremic syndrome (HUS) [6,7,8]. Cattle are the primary natural reservoir acting as symptomless carriers [9,10,11], although Stx is capable of exerting cytotoxic effects, e.g., on bovine lymphocytes [12,13,14].…”

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

“…Median age of patients was 22 months and 33 (48.5%) were females. Time from first symptoms to STEC-HUS diagnosis was 5 days ( 2 – 9 ); bloody diarrhea was found in 86.8% of cases ( n = 59). By stool culture and/or anti-lipopolysaccharide antibodies, serogroup O26 accounted for 38 cases, O111 for 13 cases, O145 for 9 case, O103 and O157 for 3 each.…”

“…In our study baseline serum levels of C3 fraction, but not C4, were significantly lower in patients with neurologic involvement. Although decreased C4 levels have been occasionally reported in some patients (23,48), its significance remains unclear probably due to the lack of evidence in the activation of classical and/or lectin pathways in STEC-HUS (9,14,22,49).…”

“…The endothelial damage caused by Shiga toxin (Stx) is more likely to be the culprit pathogenic mechanism of the disease ( 8 ); however, there is increasing evidence for complement system activation as a contributing factor involved in organ damage ( 9 ). Several reports during last decades have described low plasma C3 concentrations and augmented complement products' degradation in children affected by STEC-HUS ( 10 – 12 ).…”