Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

Abstract

Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement-and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(؊)؉4, ؉6A, ؉7F, and ؉23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(؊)؉6A and ؉23F strains compared to ؉7F and ؉4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(؊)؉6A and ؉23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(؊)؉6A and ؉23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.

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

“…We found that complement deposition on pneumococci correlates with the anticapsular antibody concentration required for opsonophagocytic killing: the serotypes that were least resistant to C3 deposition required the lowest concentration of capsule antibodies. TIGR4 serotypes 4 and 7F have previously been reported to be more resistant to C3 deposition than serotypes 6A and 23F (16), whereas in the present study TIGR4 serotype 4 was less resistant than 23F. Since the mutants of these two studies were constructed independently, the source of the TIGR4 parent strain (serotype 4) could affect the results.…”

“…Although nonopsonic phagocytic receptors can mediate phagocytosis directly (51), neutrophil phagocytosis is markedly increased by opsonization of pneumococcus with complement (56). Complement deposition on TIGR4 mutants expressing different serotypes correlated with neutrophil phagocytosis in the presence of complement, but differences in phagocytosis between strains were abolished when the bacteria were not opsonized with complement (16). We found that complement deposition on pneumococci correlates with the anticapsular antibody concentration required for opsonophagocytic killing: the serotypes that were least resistant to C3 deposition required the lowest concentration of capsule antibodies.…”

“…We found significant variation in the magnitude of complement deposition between isolates expressing the same capsular serotype, suggesting a role of serotype-independent factors in the outcome of this particular interaction. In a recent study by Hyams et al (16) comparing C3 deposition on TIGR4 capsule-switch mutants, the resistance of pneumococcus to complement-mediated immunity was found to vary with the capsular serotype independently of capsular thickness or antibody binding. In the present study, we assessed the influence of the capsular serotype on complement deposition and opsonophagocytic killing by comparing several isogenic capsule-switched mutants and clonally related clinical isolates sharing the same sequence type but expressing different capsular polysaccharides (natural capsule switch variants of the same pneumococcal strain).…”

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

“…While these characteristics might partly be related to the expression of a non-pore-forming PLY, the overall characteristic of a given pneumococcal type (colonizer/cause of invasive disease) is certainly the sum of different features and clearly depends on variations of other bacterial factors including the capsular polysaccharides (56,57).…”

Capsule Contributes to Transmigration of Streptococcus pneumoniae Serotype 7F Meningitis Isolates through Complex Blood Brain Barrier Models

“…Amount and composition of polysaccharide capsule expression is used to distinguish between up to 94 pneumococcal serotypes (oral communication with Dr. M. van der Linden, NRZ Aachen). Each serotype is characterized by an individual polysaccharide capsule, which mediates the escape from phagocytosis or complement factor binding and prevents entrapment by neutrophil extracellular traps [9][10][11][12][13]. The predominant serotypes associated with severe pneumococcal diseases vary with respect to geographical and demographical situation and respective vaccination programs.…”