In Vivo Binding of Complement Regulator Factor H byStreptococcus pneumoniae

Abstract

Pneumococcal surface protein C (PspC) binds to the complement regulatory protein factor H (FH), which inhibits alternative pathway activation. In the present study, using a mouse model of systemic infection and flow-cytometri analyses, we demonstrated an in vivo interaction between FH and pneumococci and showed differential FH binding during bacteremia. Flow-cytometric analyses of pneumococci harvested after intraperitoneal (ip) challenge demonstrated increased binding of FH, compared with that after intravenous (iv) challenge. Real-time polymerase chain reaction analyses of PspC mRNA showed that, relative to pneumococci grown in vitro, those recovered from the blood of mice 24 h after iv challenge exhibited 23-fold higher mRNA levels; however, after ip challenge, PspC mRNA induction was increased 870-fold. A subsequent increase in PspC expression was detected by flo cytometry using a monoclonal antibody against PspC. Furthermore, pneumococci with FH bound to complement before exposure had increased proliferation, compared with pneumococci not pretreated with FH. These results suggest that the interaction between PspC and FH contributes to pneumococcal virulence.Streptococcus pneumoniae remains the principal causative agent of otitis media, pneumonia, and meningitis in both children and adults [1]. The pneumococcus is an extracellular pathogen that uses virulence factors, such as its polysaccharide capsule, to inhibit ingestion and subsequent killing by phagocytes [1,2]. The expression of several virulence-associated proteins-including the choline-binding pneumococcal surface proteins A [3,4] and C (PspC; also referred to as "CbpA" and "SpsA") [5][6][7], as well as pneumolysin [8]-also contribute to this organism's capacity to hinder im-

Versatility of pneumococcal surface proteins

“…Recruitment of factor H by Hic has been shown to efficiently prevent activation of C3b and complement-mediated opsonophagocytosis of pneumococci (Jarva et al, 2004). The improved survival of pneumococci expressing PspC or Hic in a systemic mouse infection model provides further evidence for the versatility and importance of PspC in different host niches (Iannelli et al, 2004;Quin et al, 2005).…”

The Capsular Serotype ofStreptococcus pneumoniaeIs More Important than the Genetic Background for Resistance to Complement

“…Pneumolysin depletes complement by activating the classical pathway at a distance from the bacterium (54). The pneumococcal surface protein C (PspC) inhibits the activation of complement by, e.g., binding factor H (7,8), a serum protein that efficiently modulates the function of the complement (17,18,38). The genetic background is likely to affect the relative importance of a surface protein to the complement resistance of the strain.…”

Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces

“…In addition to its function as a regulator of alternative pathway activation in plasma, factor H also binds to human endothelial cells and basement membranes (18), protecting them from complementmediated attack (19). Moreover, some cancer cell surfaces (20,21) and pathogenic microorganisms (22)(23)(24)(25)(26)(27) have developed immune evasion strategies whereby they bind factor H, thus disguising themselves as self cells and escaping elimination by the alternative pathway of complement. In a factor H-deficient line of pigs, homozygous individuals die soon after birth from complement-mediated acute renal failure (28), and factor H-deficient mice develop membranoproliferative glomerulonephritis, which was shown to be alternative pathway dependent (19).…”