Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening
Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening
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DOI：
10.1073/pnas.1613937114
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发表时间：
2017-01-17
影响因子：
11.1
通讯作者：
Lipsitch, Marc
中科院分区：
文献类型：
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作者：
Croucher, Nicholas J.;Campo, Joseph J.;Lipsitch, Marc
描述肺炎球菌蛋白质的免疫反应对于了解这种细菌的流行病学和疫苗学至关重要。用来自35名健康美国成年人的血清探测定制设计的蛋白质组微阵列，揭示了来自全物种泛基因组的2，190种潜在抗原的IgG亲和力的连续分布。通过208种“抗体结合靶点”（ABT），其中包括109种不同的肺炎球菌表面蛋白A和C（PspA和PspC）以及锌金属蛋白酶A和B（ZmpA和Zmp B）蛋白的变体，引发了可重复升高的IgG结合。功能分析发现ABT富含分泌和细胞表面缔合的基序，具有细胞壁合成机制、粘附素、转运蛋白溶质结合蛋白和降解酶的广泛代表性。ABT与正选择下进化的更强有力的证据相关，尽管这在功能类别之间存在差异，通过重组的多样化率也是如此。在一些免疫原性的辅助位点，包括噬菌体蛋白和相位可变的糖基转移酶无处不在的不同的一组基因组岛屿编码富含丝氨酸的PsrP糖蛋白，观察到特别快速的变化。然而，许多抗原在核心基因组中是保守的，并且菌株的抗原谱通常是稳定的。没有发现强有力的证据表明驱动群体动态的抗原之间存在任何上位性，或功能相似的辅助ABT之间存在冗余，或抗原谱的年龄分层。这些结果突出了为什么仅在表位的子集中观察到实质性变化的矛盾。这一结果可能表明，只有一些免疫球蛋白和ABT之间的相互作用，清除肺炎球菌定植或获得性免疫肺炎球菌是一个积累的个别弱反应ABT演变下不同水平的功能限制。
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 inmotifs 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.