title: Pneumococcal surface protein A inhibits complement deposition on the pneumococcal surface by competing with the binding of C-reactive protein to cell-surface phosphocholine.
abstract: In the presence of normal serum, complement component C3 is deposited on pneumococci primarily via the classical pathway. Pneumococcal surface protein A (PspA), a major virulence factor of pneumococci, effectively inhibits C3 deposition. PspA's C terminus has a choline-binding domain that anchors PspA to the phosphocholine (PC) moieties on the pneumococcal surface. C-reactive protein (CRP), another important host defense molecule, also binds to PC, and CRP binding to pneumococci enhances complement C3 deposition through the classical pathway. Using flow cytometry of PspA(+) and PspA(-) strains, we observed that the absence of PspA led to exposure of PC, enhanced the surface binding of CRP, and increased the deposition of C3. Moreover, when the PspA(-) mutant was incubated with a pneumococcal eluate containing native PspA, there was decreased deposition of CRP and C3 on the pneumococcal surface compared with incubation with an eluate from a PspA(-) strain. This inhibition was not observed when a recombinant PspA fragment, which lacks the choline-binding region of PspA, was added to the PspA(-) mutant. Also, there was much greater C3 deposition onto the PspA(-) pneumococcus when exposed to normal mouse serum from wild-type mice as compared with that from CRP knockout mice. Furthermore, when CRP knockout mouse serum was replenished with CRP, there was a dose-dependent increase in C3 deposition. The combined data reveal a novel mechanism of complement inhibition by a bacterial protein: inhibition of CRP surface binding and, thus, diminution of CRP-mediated complement deposition.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 24294, USA.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Mukerji
authors.forename: Shaper
authors.initials: S
authors.lastname: Mirza
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Roche
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Widener
authors.forename: Christina M
authors.initials: CM
authors.lastname: Croney
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D003470:Culture Media; D006801:Humans; D051379:Mice; D010767:Phosphorylcholine / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D003176:Complement C3; D003470:Culture Media; D011994:Recombinant Proteins; C051592:pneumococcal surface protein A; D010767:Phosphorylcholine; D002097:C-Reactive Protein