The pneumococcal surface proteins PspA and PspC sequester host C4 binding protein to inactivate complement C4b on the bacterial surface.

Complement is a critical component of antimicrobial immunity. Various complement regulatory proteins prevent host cells from being attacked. Many pathogens have acquired the ability to sequester complement regulators from host plasma to evade complement attack. Here we describe how Streptococcus pneumoniae adopts a strategy to prevent the formation of the C3 convertase, C4bC2a, by the rapid conversion of surface bound C4b and iC4b into C4dg, which remains bound to the bacterial surface but no longer forms a convertase complex. Non-capsular virulence factors on the pneumococcus are thought to facilitate this process by sequestering C4b-binding protein (C4BP) from host plasma.When S. pneumoniae D39 was opsonised with human serum, the larger C4 activation products, C4b and iC4b, were undetectable, but the bacteria were liberally decorated with C4dg and C4BP. With targeted deletions of either PspA, or PspC, C4BP deposition was markedly reduced and there was a corresponding reduction in C4dg, and an increase in the deposition C4b and iC4b. The effect was greatest when PspA and PspC were both knocked out. Infection experiments in mice indicated that the deletion PspA and/or PspC resulted in the loss of bacterial pathogenicity. Recombinant PspA and PspC both bound serum C4BP, and both led to increased C4b and reduced C4dg deposition on S. pneumoniae D39. We conclude that PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b. Importance Streptococcus pneumoniae (the pneumococcus) causes pneumonia, septicemia and meningitis, claiming for more than a million lives every year. In common with many other pathogens, the pneumococcus has evolved mechanisms to avoid attack by the human immune system. Complement activation is a part of the immune response to pneumococcal infection. When complement is activated the pathogen becomes coated in complement proteins, chiefly C4b and C3b, which target it for clearance by phagocytes. The pneumococcal surface proteins PspA and PspC are known to inhibit the host complement system.Using pneumococci deficient in PspA and PspC, and recombinant forms of both proteins, we demonstrate that PspA and PspC sequester a host complement regulatory protein called C4BP. The physiological role of C4BP is to facilitate the breakdown of complement C4b. By recruiting C4BP to the bacterial surface, the pneumococcus accelerates the breakdown of C4b, thus helping it to avoid phagocytosis.