Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.
Infections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factors of EHEC, contributing to HUS pathogenesis. Beside EHEC-associated HUS, there are hereditary atypical forms of HUS, which are mostly caused by mutations of complement regulators. The aim of the present study was to investigate whether or not complement is also involved in the pathogenesis of EHEC-induced typical HUS, by being activated either directly or indirectly by involvement of its inhibitors. Purified Stx2 markedly activated complement via the alternative pathway and was found to bind to factor H (FH), however, only when it was active. No apparent cleavage or destruction of FH was visible, and cofactor activity in fluid phase was unaffected, but clearly delayed for surface-attached FH, where it is essential for host cell protection. Binding studies using FH constructs revealed that Stx2 binds to short consensus repeats (SCRs) 6-8 and SCRs18-20, but not to SCRs16-17, i.e., to regions involved in the surface recognition function of FH. In conclusion, complement, and in particular FH, not only plays an important role in atypical HUS, but most probably also in EHEC-induced HUS.
Department of Hygiene, Innsbruck Medical University and Austrian Reference Centre for Enterohaemorrhagic Escherichia coli, Innsbruck, Austria.
Dorothea
D
Orth
Abdul Basit
AB
Khan
Asma
A
Naim
Katharina
K
Grif
Jens
J
Brockmeyer
Helge
H
Karch
Michael
M
Joannidis
Simon J
SJ
Clark
Anthony J
AJ
Day
Sonja
S
Fidanzi
Heribert
H
Stoiber
Manfred P
MP
Dierich
Lothar B
LB
Zimmerhackl
Reinhard
R
Würzner
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D003167:Complement Activation / Q000502:physiology*; D017242:Complement Factor H / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D054324:Enterohemorrhagic Escherichia coli; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000150:complications; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D047468:Immunoprecipitation; D022621:Shiga Toxin / Q000378:metabolism*
D022621:Shiga Toxin; D017242:Complement Factor H