title: Interaction of Shiga toxin 2 with complement regulators of the factor H protein family.
abstract: Shiga toxin 2 (Stx2) is believed to be a major virulence factor of enterohemorrhagic Escherichia coli (EHEC) contributing to hemolytic uremic syndrome (HUS). The complement system has recently been found to be involved in the pathogenesis of EHEC-associated HUS. Stx2 was shown to activate complement via the alternative pathway, to bind factor H (FH) at short consensus repeats (SCRs) 6-8 and 18-20 and to delay and reduce FH cofactor activity on the cell surface. We now show that complement factor H-related protein 1 (FHR-1) and factor H-like protein 1 (FHL-1), proteins of the FH protein family that show amino acid sequence and regulatory function similarities with FH, also bind to Stx2. The FHR-1 binding site for Stx2 was located at SCRs 3-5 and the binding capacity of FHR-1*A allotype was higher than that of FHR-1*B. FHR-1 and FHL-1 competed with FH for Stx2 binding, and in the case of FHR-1 this competition resulted in a reduction of FH cofactor activity. FHL-1 retained its cofactor activity in the fluid phase when bound to Stx2. In conclusion, multiple interactions of key complement inhibitors FH, FHR-1 and FHL-1 with Stx2 corroborate our hypothesis of a direct role of complement in EHEC-associated HUS.
authors: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria.
authors: Kulwara
authors: K
authors: Poolpol
authors: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria. Electronic address: dorothea.orth@i-med.ac.at.
authors: Dorothea
authors: D
authors: Orth-Höller
authors: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria.
authors: Cornelia
authors: C
authors: Speth
authors: Leibniz Institute for Natural Product Research and Infection Biology, Department of Infection Biology, Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Peter F
authors: PF
authors: Zipfel
authors: Leibniz Institute for Natural Product Research and Infection Biology, Department of Infection Biology, Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Christine
authors: C
authors: Skerka
authors: Centre for Biological Research, Spanish Scientific Research Council (CSIC) and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors: Santiago Rodriguez
authors: SR
authors: de Córdoba
authors: Institute of Food Chemistry, University of Münster, Corrensstr. 45, 48149 Münster, Germany.
authors: Jens
authors: J
authors: Brockmeyer
authors: Institute for Hygiene and the National Consulting Laboratory on Hemolytic Uremic Syndrome, University of Münster, Robert Koch Str. 41, 48149 Münster, Germany.
authors: Martina
authors: M
authors: Bielaszewska
authors: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria. Electronic address: reinhard.wuerzner@i-med.ac.at.
authors: Reinhard
authors: R
authors: Würzner
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics / Q000276:immunology*; D003180:Complement C3b Inactivator Proteins / Q000235:genetics / Q000276:immunology*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology*; D054324:Enterohemorrhagic Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D011485:Protein Binding / Q000276:immunology; D022641:Shiga Toxin 2 / Q000276:immunology*
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D022641:Shiga Toxin 2; C100631:factor H-related protein 1; D017242:Complement Factor H
keywords: Complement regulatory proteins; EHEC; FH; FHL-1; FHR-1; FI; Factor H; Factor H-like protein 1; Factor H-related protein 1; HUS; Hemolytic uremic syndrome; MCP; SCRs; Shiga toxin; Stx; TCC; aHUS; atypical HUS; enterohemorrhagic Escherichia coli; factor H; factor H-like protein 1; factor H-related protein 1; factor I; heat-inactivated Stx; hemolytic uremic syndrome; hi-Stx; membrane cofactor protein; short consensus repeats; terminal complement complex