Logarithmic phase Escherichia coli K1 efficiently avoids serum killing by promoting C4bp-mediated C3b and C4b degradation.
Meningitis caused by Escherichia coli K1 is a serious illness in neonates with neurological sequelae in up to 50% of survivors. A high degree of bacteremia is required for E. coli K1 to cross the blood-brain barrier, which suggests that the bacterium must evade the host defence mechanisms and survive in the bloodstream. We previously showed that outer membrane protein A (OmpA) of E. coli binds C4b-binding protein (C4bp), an inhibitor of complement activation via the classical pathway. Nevertheless, the exact mechanism by which E. coli K1 survives in serum remains elusive. Here, we demonstrate that log phase (LP) OmpA+ E. coli K1 avoids serum bactericidal activity more effectively than postexponential phase bacteria. OmpA- E. coli cannot survive in serum grown to either phase. The increased serum resistance of LP OmpA+ E. coli is the result of increased binding of C4bp, with a concomitant decrease in the deposition of C3b and the downstream complement proteins responsible for the formation of the membrane attack complex. C4bp bound to E. coli K1 acts as a cofactor to factor I in the cleavage of both C3b and C4b, which shuts down the ensuing complement cascade. Accordingly, a peptide corresponding to the complement control protein domain 3 of C4bp sequence, was able to compete with C4bp binding to OmpA and cause increased deposition of C3b. Thus, binding of C4bp appears to be responsible for survival of E. coli K1 in human serum.
Division of Infectious Diseases, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
David G
DG
Wooster
Ravi
R
Maruvada
Anna M
AM
Blom
Nemani V
NV
Prasadarao
D000942:Antigens, Bacterial / Q000096:biosynthesis; D016667:Bacterial Capsules; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D001770:Blood Bactericidal Activity / Q000276:immunology*; D015153:Blotting, Western; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000276:immunology*; D015935:Complement C4b / Q000276:immunology*; D050716:Complement C4b-Binding Protein / Q000276:immunology; D004926:Escherichia coli / Q000254:growth & development / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008074:Lipoproteins / Q000276:immunology; D020814:Meningitis, Escherichia coli; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D050716:Complement C4b-Binding Protein; D008074:Lipoproteins; C094096:OmlA protein, bacteria; D011135:Polysaccharides, Bacterial; C036962:capsular polysaccharide K1; D003179:Complement C3b; D015935:Complement C4b