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

• Published in: mBio Vol. 9; no. 2
• Main Authors: Georgieva, M, Kagedan, L, Lu, Ying-Jie, Thompson, C M, Lipsitch, M
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 13.03.2018
• Subjects: Antibodies, Bacterial - immunology; Antibodies, Bacterial - metabolism; Antigenic Variation; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Blood Bactericidal Activity; Complement Factor H - metabolism; Humans; Immune Evasion; Phagocytosis; Pneumococcal Infections - immunology; Protein Binding; Streptococcus pneumoniae - genetics; Streptococcus pneumoniae - immunology; PspC; antigenic variation; Streptococcus pneumoniae
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00264-18

Genomic analysis reveals extensive sequence variation and hot spots of recombination in surface proteins of 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 Here, we investigate the biological significance of sequence variation within the cell wall-associated pneumococcal surface protein C (PspC) protein antigen. Using allelic diversity observed in a large pneumococcal collection, we produced variant-specific protein constructs that span the sequence variability within the 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 reflects differences in biological function. Finally, in an antibody-dependent opsonophagocytic assay, expressing a PspC variant matching the antibody specificity was killed efficiently. In contrast, killing efficacy was not evident against 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. Loci encoding surface protein antigens in are highly polymorphic. It has become a truism that these polymorphisms are the outcome of selective pressure on to escape host immunity. However, there is little mechanistic evidence to support the hypothesis that diversifying protein antigens produces a benefit for the bacteria. Using the highly diverse locus, we have now characterized the functional and immune implications of sequence diversity within the PspC protein. We have characterized the spectrum of biological function among diverse PspC variants and show that sequence diversity reflects functional differences. Further, we show that sequence variation in PspC confers an immune escape benefit in the presence of anti-PspC variant-specific immunity. Overall, the results of our studies provide insights into the functional implications of protein sequence diversity and the role of variant-specific immunity in its maintenance.