Pneumococcal Surface Protein A Inhibits Complement Activation byStreptococcus pneumoniae

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 α 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.

The pavA gene of Streptococcus pneumoniae encodes a fibronectin‐binding protein that is essential for virulence

“…The antiphagocytic and cytotoxic effects of capsular polysaccharide and pneumolysin, respectively, prevent immune cell-mediated clearance, while autolysis results in the release of cell-wall fragments that provoke intense inflammation. Surface protein PspA has recently been shown to also affect clearance of pneumococci by inhibiting deposition of complement C3b onto cells (Tu et al, 1999). In identifying PavA as an adhesin and as a virulence factor, we suggest that this polypeptide may function at more than one stage in the infection process.…”

“…PspA is a cell-surface-associated protein, the N-terminal domain of which binds lactoferrin (Hammerschmidt et al, 1999;Hakansson et al, 2001). PspA functions as an inhibitor of factor B-mediated complement activation (Tu et al, 1999), interfering with deposition of C3b and therefore reducing susceptibility of pneumococci to opsonophagocytosis. PspA is a member of the family of choline-binding proteins (CBPs) that are non-covalently attached to the pneumococcal cell surface (Yother and White, 1994).…”

Complement: a critical test of its biological importance

“…That is, in wild-type mice, PspA-deficient stains, but not PspA-expressing strains, are cleared rapidly. In C3 or factor B knockout mice, the PspA-negative pneumococci are fully virulent (74). C3 and C4 knockout mice were used to demonstrate that the defense against group B streptococci depends primarily on alternative pathway complement activation (72).…”

Preliminary study on the application of PspA as carrier

“…In order to solve the above problems, we chose pneumococcal surface protein A (PspA) as research subject. PspA is virulence associated protein found on the surface of all clinical isolates of S. pneumonia (3) and interferes with opsonophagocytosis by interfering with complement deposition on the bacterial surface (4,5). It has five domains: a single peptide, α-helical and charged N-terminal domain, a proline-rich region, a choline-binding domain and a short hydrophobic tail.…”

“…According to the sequences of α-helical region, PspAs have been divided into six clades, which belong to three families (6, 7). PspA family 1 contains two clades (1 and 2), PspA family 2 contains three clades (3, 4 and 5) and PspA family 3 contains one clade (clade 6). Families 1 and 2 are expressed in more than 90 percent of strains (8).…”