Abstract
ABSTRACTGenomic 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.
Highlights
Genomic analysis reveals extensive sequence variation and hot spots of recombination in surface proteins of Streptococcus pneumoniae
We selected four pneumococcal surface protein C (PspC) variants that span the range of genetic diversity of the pspC locus within this pneumococcal population [5, 23, 31]
We recently reported the presence of naturally acquired antibodies against these four PspC variants in individuals colonized with S. pneumoniae [23]
Summary
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. We investigate the biological significance of sequence variation within the S. pneumoniae cell wall-associated pneumococcal surface protein C (PspC) protein antigen. Using the highly diverse pspC locus, we have characterized the functional and immune implications of sequence diversity within the PspC protein. Despite a growing body of evidence pointing to extensive sequence variation in pneumococcal surface protein antigens, we know little about the immune and functional implications of this diversity. The association between PspC and the fH and C3 complement mediators seems to play an important role at various stages of the in vivo biology of the pneumococcus [15,16,17,18,19,20,21,22]
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