Understanding the bacterial polysaccharide antigenicity of Streptococcus agalactiae versus Streptococcus pneumoniae
Understanding the bacterial polysaccharide antigenicity of Streptococcus agalactiae versus Streptococcus pneumoniae
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DOI：
10.1073/pnas.0602815103
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发表时间：
2006-05-23
影响因子：
11.1
通讯作者：
Woods, Robert J.
中科院分区：
文献类型：
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作者：
Kadirvelraj, Renuka;Gonzalez-Outeirino, Jorge;Woods, Robert J.
碳水化合物序列相似的细菌表面被膜多糖(CP)在免疫原性和抗原性方面可能存在明显差异。人们对这些现象的结构性根源知之甚少。这种病例是由革兰氏阳性菌无乳链球菌(B群链球菌；GBS)III型(GBSIII)和肺炎链球菌(PN)14型(Pn14)提出的，它们具有密切相关的CPS序列。然而，抗GBSIII的抗体很少与来自Pn14的CP发生交叉反应。为了确定CPS抗原性变异的来源，建立了GBSIII和Pn14的CPS片段与GBS特异性mAb(MAb1b1)的可变片段(Fv)的免疫复合物模型。这些络合物是通过比较分子轨道建模和自动配基对接的组合产生的，随后是显式求解的10 ns分子动力学模拟。通过分子力学-广义玻恩表面积(MM-GBSA)方法计算相互作用能，并结合构象熵估计，进一步量化了碳水化合物序列与抗原性之间的关系。尽管Pn14和GBSIII CPS之间存在静电差异，但分析表明，熵惩罚是导致高度灵活的Pn14 CPS与mAb1b1失去亲和力的主要原因。相对刚性的GBSIII CPS的溶液构象与免疫复合物中的溶液构象的相似性表征了先前未描述的构象表位的3D结构。该分析为大量与抗体识别细菌多糖相关的生化和免疫学数据提供了全面的解释，并应适用于其他抗体-碳水化合物的相互作用。
Bacterial surface capsular polysaccharides (CPS) that are similar in carbohydrate sequence may differ markedly in immunogenicity and antigenicity. The structural origin of these phenomena is poorly understood. Such a case is presented by the Gram-positive bacteria Streptococcus agalactiae (Group B Streptococcus; GBS) type III (GBSIII) and Streptococcus pneumoniae (Pn) type 14 (Pn14), which share closely related CPS sequences. Nevertheless, antibodies (Abs) against GBSIII rarely cross-react with the CPS from Pn14. To establish the origin for the variation in CPS antigenicity, models for the immune complexes of CPS fragments from GBSIII and Pn14, with the variable fragment (Fv) of a GBS-specific mAb (mAb 1B1), are presented. The complexes are generated through a combination of comparative Ab modeling and automated ligand docking, followed by explicitly solvated 10-ns molecular dynamics simulations. The relationship between carbohydrate sequence and antigenicity is further quantified through the computation of interaction energies using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method, augmented by conformational entropy estimates. Despite the electrostatic differences between Pn14 and GBSIII CPS, analysis indicates that entropic penalties are primarily responsible for the loss of affinity of the highly flexible Pn14 CPS for mAb 1B1. The similarity of the solution conformation of the relatively rigid GBSIII CPS with that in the immune complex characterizes the previously undescribed 3D structure of the conformational epitope. The analysis provides a comprehensive interpretation for a large body of biochemical and immunological data related to Ab recognition of bacterial polysaccharides and should be applicable to other Ab-carbohydrate interactions.