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Role of serum amyloid P component in bacterial infection: Protection of the host or protection of the pathogen

2000; National Academy of Sciences; Volume: 97; Issue: 26 Linguagem: Inglês

10.1073/pnas.97.26.14584

1091-6490

Mahdad Noursadeghi, Maria C. M. Bickerstaff, J. Ruth Gallimore, Jeff Herbert, Jonathan Cohen, Mark B. Pepys,

Pneumonia and Respiratory Infections

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.