Antigenic Variation in Streptococcus pneumoniae PspC Promotes Immune Escape in the Presence of Variant-Specific Immunity

Genomic analysis reveals extensive sequence variation and hot spots of recombination in surface proteins of Streptococcus pneumoniae. While this phenomenon is commonly attributed to diversifying selection by host immune responses, there is little mechanistic evidence for the hypothesis that diversification of surface protein antigens produces an immune escape benefit during infection with S. pneumoniae. Here, we investigate the biological significance of sequence variation within the S. pneumoniae cell wall-associated pneumococcal surface protein C (PspC) protein antigen. Using pspC allelic diversity observed in a large pneumococcal collection, we produced variant-specific protein constructs that span the sequence variability within the pspC locus. We show that antibodies raised against these PspC constructs are variant specific and prevent association between PspC and the complement pathway mediator, human factor H. We found that PspC variants differ in their capacity to bind factor H, suggesting that sequence variation within pspC reflects differences in biological function. Finally, in an antibody-dependent opsonophagocytic assay, S. pneumoniae expressing a PspC variant matching the antibody specificity was killed efficiently. In contrast, killing efficacy was not evident against S. pneumoniae expressing mismatched PspC variants. Our data suggest that antigenic variation within the PspC antigen promotes immune evasion and could confer a fitness benefit during infection.