Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening
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Croucher, Nicholas J.
Campo, Joseph J.
Le, Timothy Q.
Bentley, Stephen D.
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CitationCroucher, Nicholas J., Joseph J. Campo, Timothy Q. Le, Xiaowu Liang, Stephen D. Bentley, William P. Hanage, and Marc Lipsitch. 2017. “Diverse Evolutionary Patterns of Pneumococcal Antigens Identified by Pangenome-Wide Immunological Screening.” Proceedings of the National Academy of Sciences 114 (3) (January 4): E357–E366. doi:10.1073/pnas.1613937114.
AbstractCharacterizing the immune response to pneumococcal proteins is critical in understanding this bacterium's epidemiology and vaccinology. Probing a custom-designed proteome microarray with sera from 35 healthy US adults revealed a continuous distribution of IgG affinities for 2,190 potential antigens from the species-wide pangenome. Reproducibly elevated IgG binding was elicited by 208 "antibody binding targets" (ABTs), which included 109 variants of the diverse pneumococcal surface proteins A and C (PspA and PspC) and zinc metalloprotease A and B (ZmpA and ZmpB) proteins. Functional analysis found ABTs were enriched in motifs for secretion and cell surface association, with extensive representation of cell wall synthesis machinery, adhesins, transporter solute-binding proteins, and degradative enzymes. ABTs were associated with stronger evidence for evolving under positive selection, although this varied between functional categories, as did rates of diversification through recombination. Particularly rapid variation was observed at some immunogenic accessory loci, including a phage protein and a phase-variable glycosyltransferase ubiquitous among the diverse set of genomic islands encoding the serine-rich PsrP glycoprotein. Nevertheless, many antigens were conserved in the core genome, and strains' antigenic profiles were generally stable. No strong evidence was found for any epistasis between antigens driving population dynamics, or redundancy between functionally similar accessory ABTs, or age stratification of antigen profiles. These results highlight the paradox of why substantial variation is observed in only a subset of epitopes. This result may indicate only some interactions between immunoglobulins and ABTs clear pneumococcal colonization or that acquired immunity to pneumococci is an accumulation of individually weak responses to ABTs evolving under different levels of functional constraint.
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