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.
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Authors | Kulwara Poolpol, Dorothea Orth-Höller, Cornelia Speth, Peter F Zipfel, Christine Skerka, Santiago Rodriguez de Córdoba, Jens Brockmeyer, Martina Bielaszewska, Reinhard Würzner |
Journal | Molecular immunology
(Mol Immunol)
Vol. 58
Issue 1
Pg. 77-84
(Mar 2014)
ISSN: 1872-9142 [Electronic] England |
PMID | 24317278
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Ltd. All rights reserved. |
Chemical References |
- Blood Proteins
- CFHR1 protein, human
- Complement C3b Inactivator Proteins
- Shiga Toxin 2
- factor H-related protein 1
- Complement Factor H
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Topics |
- Amino Acid Sequence
- Binding Sites
- Blood Proteins
(genetics, immunology)
- Complement C3b Inactivator Proteins
(genetics, immunology)
- Complement Factor H
(genetics, immunology)
- Enterohemorrhagic Escherichia coli
(pathogenicity)
- Escherichia coli Infections
(immunology, microbiology, pathology)
- Hemolytic-Uremic Syndrome
(immunology, microbiology, pathology)
- Humans
- Protein Binding
(immunology)
- Shiga Toxin 2
(immunology)
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