The role of pneumococcal surface protein A in virulence of a capsular serotype 3 Streptococcus pneumoniae: Complement attack versus bacterial evasion

Complement plays an important role in host immunity against pneumococcal infections. Pneumococcal surface protein A (PspA) is a virulence factor of pneumococci, and also a promising candidate for pneumococcal protein-based vaccine. Based on their sequence homology, PspA molecules have been divided into three major families. Previous studies have shown that family 1 PspA is important for the virulence of WU2, a capsular serotype 3 strain, and it inhibits complement deposition on the pneumococcal surface. PspAs of family 1 and 2 share 40% homology in their N-terminal alpha-helical region. To determine whether these two family PspAs play similar roles in virulence, a family 2 PspA from the TIGR4 strain (capsular type 4) was introduced into WU2 to replace the original family 1 PspA. Our results showed that on the WU2 background, both family 1 and 2 PspAs have the same influence on complement deposition and virulence in a murine bacteremia model.; Complement activation can be triggered by two major pathways: the classical/MBL and alternative pathways. It was revealed that mainly the classical pathway initiates the deposition of C3 on the surface of the capsular type 3 strain, while the alter native pathway is important for amplifying C3 activation and deposition triggered via the classical pathway. The difference in C3 deposition onto strains WU2 (pspA+) and JY1119 ( pspA-) in the presence of antibodies to capsular type 3 and factor-B-deficient mouse serum suggests that PspA may interfere with the classical-pathway-mediated C3 deposition. Both human and mouse antibodies to PspA significantly increased the C3 deposition on the surface of WU2.; The roles of complement receptors in the pneumococcal infection were investigated using mutant mice deficient in complement receptors. Our results suggest that complement receptor 1, 3 and 4 play essential roles in elimination of bacteria from the host blood stream. Our results also confirmed the important role of the alternative pathway in host defense against pneumococcal infection, since factor-D-deficient mice challenged with either WU2 or JY1119 showed significantly decreased survival time as compared to wild-type mice.