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Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome¹

Dorothea Orth^2,*, Abdul Basit Khan^2,*, Asma Naim^*, Katharina Grif^*, Jens Brockmeyer, Helge Karch, Michael Joannidis, Simon J. Clark, Anthony J. Day, Sonja Fidanzi^*, Heribert Stoiber^*, Manfred P. Dierich^*, Lothar B. Zimmerhackl^¶ and Reinhard Würzner^3,*

^* Department of Hygiene, Microbiology, and Social Medicine, Innsbruck Medical University and Austrian Reference Centre for Enterohaemorrhagic Escherichia coli, Innsbruck, Austria; Institute for Hygiene and National Consulting Laboratory on Hemolytic Uremic Syndrome, University of Münster, Münster, Germany; Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and ^¶ Department of Pediatrics 1, Innsbruck Medical University, Innsbruck, Austria

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant LSHB-CT-2005-512061 from the Network of Excellence, EuroPathoGenomics; by Grant MFF 134 from the Medizinische Forschungsförderung Innsbruck; and by Grant 20041040 from Kidneeds, Iowa.

² D.O. and A.B.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Reinhard Würzner, Department of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Fritz-Pregl-Str. 3, 6020 Innsbruck, Austria. E-mail address: reinhard.wuerzner{at}i-med.ac.at

⁴ Abbreviations used in this paper: HUS, hemolytic uremic syndrome; aHUS, atypical HUS; AP, alkaline-phosphatase; CHO, Chinese hamster ovary; EHEC, enterohemorrhagic Escherichia coli; FH, factor H; FI, factor I; hi-Stx, heat-inactivated Shiga toxin; iC3b, inactivated C3b; NHS, normal human serum; PMN, polymorphonuclear cell; SCR, short consensus repeat; Stx, Shiga toxin; TCC, terminal complement complex; VB, veronal buffer.