Clinical Isolates of Streptococcus pneumoniae Bind the Complement Inhibitor C4b-Binding Protein in a PspC Allele-Dependent Fashion

Abstract

The complement system constitutes an important component of the innate immune system. To colonize their host and/or to cause disease, many pathogens have evolved strategies to avoid complement-mediated bacterial lysis and opsonophagocytosis. In this study, using a collection of 55 clinical isolates of Streptococcus pneumoniae, we demonstrate for the first time that pneumococci bind the complement inhibitor C4b-binding protein (C4BP). C4BP binding seems to be restricted to certain serotypes such as serotype 4, 6B, 7F, and 14, of which the strains of serotype 14 are the strongest binders. We show that bacteria-bound C4BP retains its functional activity and down-regulates the activation of the classical pathway. Thus, this major respiratory pathogen may escape immune recognition and eradication by the complement system. Furthermore, we show that C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4. The study of the distribution of group 4 pspC locus shows that most of high-binder serotype 14 isolates harbor an allelic variant of group 4 pspC. Using PspC-negative mutant strains, we identified a new allelic variant of PspC (PspC4.4) as a major ligand for C4BP, revealing a new function for this important pneumococcal virulence factor. Thus pneumococci exploit host C4BP for complement evasion in a PspC allele-dependent manner.

An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

“…However, pneumococci have evolved numerous strategies for attenuation or escaping such attacks, and these mechanisms are one of the key determinants for their survival within the human host. These include recruitment of complement inhibitors such as C4BP or FH, which inhibit the classical and alternative pathway activation, respectively (6,7,41), or the expression of thick capsule, which not only inhibits the deposition of C3b but also complement-mediated opsonophagocytosis (42).…”

“…These host proteins include extracellular matrix and serum proteins such as fibronectin, thrombospondin, vitronectin, plasminogen, factor H (FH), and C4b-binding protein (C4BP) (4)(5)(6)(7)(8)(9). Pneumococcal interactions with complement inhibitors FH or C4BP protect bacteria from complement-mediated attacks (6,10). In addition, association of FH promotes pneumococcal adherence to and invasion of host cells (4,7).…”

“…These virulence factors function either as adhesins that interact directly with the host cell-surface receptors or use host protein(s) as a molecular bridge between bacteria and the host. These host proteins include extracellular matrix and serum proteins such as fibronectin, thrombospondin, vitronectin, plasminogen, factor H (FH), and C4b-binding protein (C4BP) (4)(5)(6)(7)(8)(9). Pneumococcal interactions with complement inhibitors FH or C4BP protect bacteria from complement-mediated attacks (6,10).…”

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

“…Loss of PspC had variable effects on C3 deposition depending largely on the strain background and less on the serotype (55). Binding of complement inhibitor C4b-binding protein is restricted to certain serotypes, which possess a particular PspC allele (9). Pneumococcal histidine triad proteins may also play a role in complement evasion (35), but the impact they have on complement deposition seems to depend on the genetic background (29).…”

Review: Current and new generation pneumococcal vaccines

“…129 Secondly, the adhesins, PspC and enolase, have also been reported to bind the inhibitor of the classical pathway, C4b-binding protein. 130,131 Thirdly, Ply by mechanisms distinct from pore-forming activity and which have been described in detail elsewhere, mediates activation of the classical pathway. 121 Extracellular release of the toxin is therefore likely to represent a diversionary strategy by which the pneumococcus evades innate and adaptive host defences.…”