Utilisation of staphylococcal immune evasion protein Sbi as a novel vaccine adjuvant
Utilisation of staphylococcal immune evasion protein Sbi as a novel vaccine adjuvant
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葡萄球菌免疫逃避蛋白Sbi作为新型疫苗佐剂的应用
DOI：
10.1101/413294
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Yang Y
通过C3d优化的抗原复合体将B细胞抗原受体与B细胞上的补体受体2共同连接，显著降低了B细胞激活所需的阈值。因此，抗原与C3d聚合物的融合在疫苗设计中显示出巨大的潜力。然而，这些C3d多聚体的线性阵列不能模拟抗原与C3d的自然调理。在这里，我们研究了利用葡萄球菌免疫逃避蛋白SBI独特的补体激活特性来开发一种以自然方式自发地将C3降解产物包裹在抗原上的前疫苗方法的可能性。我们发现，SBI通过补体调节因子的募集，迅速触发替代补体途径，形成三方复合体，作为H因子的竞争性拮抗剂，导致补体消耗增加。这些功能结果得到了补体激活SBI-III-IV：C3d：FHR-1复合体的结构的证实。最后，我们证明了SBI与结核杆菌抗原Ag85b融合后，可与C3片段有效地调理，从而显著增强免疫反应，大大超过单独使用Ag85b，为我们的疫苗前方法提供了概念证明。
Co-ligation of the B cell antigen receptor with complement receptor 2 on B-cells via a C3d-opsonised antigen complex significantly lowers the threshold required for B cell activation. Consequently, fusions of antigens with C3d polymers have shown great potential in vaccine design. However, these linear arrays of C3d multimers do not mimic the natural opsonisation of antigens with C3d. Here we investigate the potential of using the unique complement activating characteristics of Staphylococcal immune-evasion protein Sbi to develop a pro-vaccine approach that spontaneously coats antigens with C3 degradation products in a natural way. We show that Sbi rapidly triggers the alternative complement pathway through recruitment of complement regulators, forming tripartite complexes that act as competitive antagonists of factor H, resulting in enhanced complement consumption. These functional results are corroborated by the structure of the complement activating Sbi-III-IV:C3d:FHR-1 complex. Finally, we demonstrate that Sbi, fused withMycobacterium tuberculosisantigen Ag85b, causes efficient opsonisation with C3 fragments, thereby enhancing the immune response significantly beyond that of Ag85b alone, providing proof of concept for our pro-vaccine approach.