Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae - PubMed (original) (raw)

Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae

A H Tu et al. Infect Immun. 1999 Sep.

Abstract

Pneumococcal surface protein A (PspA) is a surface-exposed protein virulence factor for Streptococcus pneumoniae. In this study, no significant depletion of serum complement was observed for the serum of mice infected with pneumococci that express PspA. In contrast, in mice infected with an isogenic strain of pneumococci lacking PspA, significant activation of serum complement was detected within 30 min after infection. Also, the PspA-deficient strain but not the PspA-expressing strain was cleared from the blood within 6 h. The contribution of PspA to pneumococcal virulence was further investigated by using mice deficient for C5, C3, or factor B. In mice deficient for C3 or factor B, PspA-negative pneumococci became fully virulent. In contrast, in C5-deficient mice as in wild-type mice, PspA-deficient pneumococci were avirulent. These in vivo data suggest that, in nonimmune mice infected with pneumococci, PspA interferes with complement-dependent host defense mechanisms mediated by factor B. Immunoblots of pneumococci opsonized in vitro suggested that more C3b was deposited on PspA-negative than on PspA-positive pneumococci. This was observed with and without anticapsular antibody. Furthermore, processing of the alpha chain of C3b was reduced in the presence of PspA. We propose that PspA exerts its virulence function by interfering with deposition of C3b onto pneumococci and/or by inhibiting formation of a fully functional alternative pathway C3 convertase. By blocking recruitment of the alternative pathway, PspA reduces the amount of C3b deposited onto pneumococci, thereby reducing the effectiveness of complement receptor-mediated pathways of clearance.

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Figures

FIG. 1

FIG. 1

PspA inhibits complement activation and clearance of pneumococci. XID mice were infected intravenously with approximately 105 CFU of PspA+ or PspA− pneumococci, and blood was collected to quantitate bacteremia (A) and serum C3 (B). The data are presented as the means ± standard errors of the means from a total of 15 mice per group (two experiments). Asterisks indicate significant decreases in bacteremia or serum C3 concentrations compared to 0-h (preinfection) values (P < 0.05, paired t test).

FIG. 2

FIG. 2

PspA+ and PspA− pneumococci (closed and open circles, respectively) have equal virulence in C3− and FB− mice. Mice were infected intravenously with approximately 107 CFU of PspA+ or PspA− pneumococci and bled at various times thereafter to quantitate bacteremia. The data are presented as the means ± standard errors of the means for groups of two to five mice.

FIG. 3

FIG. 3

Western blot analysis of C3 deposition onto PspA+ and PspA− pneumococci. Pneumococci were exposed to XID mouse serum in the absence (lanes 2 to 8) or presence (lanes 9 to 20) of anticapsular antibody (Ab). Pneumococci were collected after exposure to XID mouse serum for 2 to 30 min (see Materials and Methods), boiled in reducing buffer, electrophoresed in SDS-polyacrylamide gels, transferred to nitrocellulose, and visualized with anti-C3 antibody. The right panel shows intact α and β chains of C3 present in normal mouse serum (NMS) and absent in C3− serum.

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