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.
Keywords
hemolytic uremic syndrome - Shiga toxin - complement - factor H family proteins -
membrane-bound complement regulators
