Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen.
Serum amyloid P component (SAP) binds to Streptococcus pyogenes, and we show here that it also binds to Neisseria meningitidis, including a lipopolysaccharide (LPS)-negative mutant, and to rough variants of Escherichia coli. Surprisingly, this binding had a powerful antiopsonic effect both in vitro and in vivo, reducing phagocytosis and killing of bacteria. Furthermore, SAP knockout mice survived lethal infection with S. pyogenes and rough E. coli J5, organisms to which SAP binds. The susceptibility of SAP(-/-) mice was fully restored by injection of isolated human SAP. However, SAP(-/-) mice were more susceptible than wild-type animals to lethal infection with E. coli O111:B4, a smooth strain to which SAP does not bind, suggesting that SAP also has some host defense function. Although SAP binds to LPS in vitro, SAP(-/-) mice were only marginally more susceptible to lethal LPS challenge, and injection of large amounts of human SAP into wild-type mice did not affect sensitivity to LPS, indicating that SAP is not a significant modulator of LPS toxicity in vivo. In contrast, the binding of SAP to pathogenic bacteria enabled them to evade neutrophil phagocytosis and display enhanced virulence. Abrogation of this molecular camouflage is thus potentially a novel therapeutic approach, and we show here that administration to wild-type mice of (R)-1-[6-(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine -2- carboxylic acid, a drug that inhibits SAP binding, significantly prolonged survival during lethal infection with E. coli J5.
Noursadeghi
M
M
Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, United Kingdom.
Bickerstaff
M C
MC
Gallimore
J R
JR
Herbert
J
J
Cohen
J
J
Pepys
M B
MB
D000818:Animals; D002478:Cells, Cultured; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008589:Meningococcal Infections / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009345:Neisseria meningitidis / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000276:immunology*; D013290:Streptococcal Infections / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*
D008070:Lipopolysaccharides; D000683:Serum Amyloid P-Component