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* Division of Infectious Diseases, Childrens Hospital, and Keck School of Medicine, University of Southern California, Los Angeles, CA 90027;
Department of Clinical Chemistry, Lund University, University Hospital Malmo, Malmo, Sweden; and
Institut National de la Santé et de la Recherche Médicale, Unité 428 University Paris V, Paris, France
Escherichia coli is an important pathogen that
causes meningitis in neonates. The development of bacteremia preceding
the traversal across the blood-brain barrier is a prerequisite for this
pathogen that obviously must survive the bactericidal activity of
serum. Here we report that outer membrane protein A (OmpA) of
Escherichia coli contributes to serum resistance by
binding to C4b binding protein (C4bp), a complement fluid phase
regulator. C4bp contains seven identical
-chains and one
-chain
linked together with disulfide bridges. We found that OmpA binds the
-chain of C4bp, which is composed of eight homologous complement
control protein (CCP) modules. Binding studies using mutants of
recombinant C4bp that lack one CCP at a time suggest that CCP3 is the
major site of interaction with OmpA. Furthermore, we demonstrate that
the N terminus of OmpA interacts with C4bp. Binding of C4bp to OmpA is
not significantly inhibited in the presence of either C4b or heparin
and is not salt sensitive, implying that it is hydrophobic in nature,
suggesting a novel interaction between OmpA and C4bp. A compelling
observation in this study is that synthetic peptides corresponding to
CCP3 sequences block the binding of C4bp to OmpA and also significantly
enhance serum bactericidal activity.
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