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7
Human antibodies to PhtD, PcpA, and Ply reduce adherence to human lung epithelial cells and murine nasopharyngeal colonization by Streptococcus pneumoniae.针对肺炎链球菌溶血素D（PhtD）、肺炎球菌黏附素A（PcpA）和肺炎球菌溶血素（Ply）的人源抗体可降低肺炎链球菌对人肺上皮细胞的黏附以及在小鼠鼻咽部的定植。
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Panel 6: Vaccines.第六面板：疫苗。
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Neutralizing antibodies elicited by a novel detoxified pneumolysin derivative, PlyD1, provide protection against both pneumococcal infection and lung injury.一种新型脱毒肺炎球菌溶血素衍生物 PlyD1 诱导产生的中和抗体可提供针对肺炎球菌感染和肺部损伤的保护。
Infect Immun. 2012 Jun;80(6):2212-20. doi: 10.1128/IAI.06348-11. Epub 2012 Apr 2.

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The protein structure initiative structural genomics knowledgebase.蛋白质结构创新计划结构基因组学知识库。
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Structure-based antigen design: a strategy for next generation vaccines.基于结构的抗原设计：下一代疫苗的策略。
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The protein folding problem.蛋白质折叠问题。
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Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense.C8α-MACPF的结构揭示了补体免疫防御中膜攻击的机制。
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A common fold mediates vertebrate defense and bacterial attack.一种常见的折叠结构介导脊椎动物防御和细菌攻击。
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Structures of perfringolysin O suggest a pathway for activation of cholesterol-dependent cytolysins.产气荚膜梭菌溶素O的结构揭示了胆固醇依赖性细胞溶素的激活途径。
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Generation and analysis of proline mutants in protein G.蛋白G中脯氨酸突变体的产生与分析。
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结构导向的抗原工程产生适合预防肺炎球菌病的肺炎球菌溶血素突变体。

Structure-guided antigen engineering yields pneumolysin mutants suitable for vaccination against pneumococcal disease.

机构信息

sanofi pasteur, Toronto, Ontario M2R 3T4, Canada.

出版信息

J Biol Chem. 2011 Apr 8;286(14):12133-40. doi: 10.1074/jbc.M110.191148. Epub 2011 Feb 4.

DOI:10.1074/jbc.M110.191148
PMID:21296887
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3069417/
Abstract

Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild-type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization.

摘要

肺炎球菌溶血素（PLY）是一种胆固醇结合、形成孔的蛋白毒素。它是肺炎链球菌的重要毒力因子，也是针对肺炎球菌病的关键疫苗靶点。我们报告了一种系统的结构驱动方法，该方法解决了该领域疫苗开发中的一个长期存在的问题：在保持 PLY 抗原完整性的同时，对其进行解毒。使用三种构象约束技术，我们合理设计了缺乏溶血活性但能诱导针对野生型毒素的中和抗体的 PLY 变体。这些结果代表了朝着广谱基于蛋白质的肺炎球菌疫苗迈出的重要一步，并说明了结构知识在制定有效的抗原优化策略方面的价值。