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Mol Immunol. 2014 Mar;58(1):77-84. doi: 10.1016/j.molimm.2013.11.009. Epub 2013 Dec 5.

Interaction of Shiga toxin 2 with complement regulators of the factor H protein family.

Author information

1
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria.
2
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria. Electronic address: dorothea.orth@i-med.ac.at.
3
Leibniz Institute for Natural Product Research and Infection Biology, Department of Infection Biology, Beutenbergstr. 11a, 07745 Jena, Germany.
4
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.
5
Institute of Food Chemistry, University of Münster, Corrensstr. 45, 48149 Münster, Germany.
6
Institute for Hygiene and the National Consulting Laboratory on Hemolytic Uremic Syndrome, University of Münster, Robert Koch Str. 41, 48149 Münster, Germany.
7
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria. Electronic address: reinhard.wuerzner@i-med.ac.at.

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.

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

PMID:
24317278
DOI:
10.1016/j.molimm.2013.11.009
[Indexed for MEDLINE]

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