title: Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening.
abstract: Characterizing 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.
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, United Kingdom; n.croucher@imperial.ac.uk.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Croucher
authors.affiliation: Antigen Discovery Inc., Irvine, CA 92618.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Campo
authors.affiliation: Antigen Discovery Inc., Irvine, CA 92618.
authors.forename: Timothy Q
authors.initials: TQ
authors.lastname: Le
authors.affiliation: Antigen Discovery Inc., Irvine, CA 92618.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Liang
authors.affiliation: Infection Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
authors.affiliation: Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
authors.forename: William P
authors.initials: WP
authors.lastname: Hanage
authors.affiliation: Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Marc
authors.initials: M
authors.lastname: Lipsitch
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology; D000328:Adult; D000907:Antibodies, Bacterial / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D026901:Membrane Transport Proteins / Q000276:immunology; D011008:Pneumococcal Infections / Q000276:immunology; D022242:Pneumococcal Vaccines / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D022242:Pneumococcal Vaccines
keywords: epidemiology; evolution; genomics; immunology; pathogens