Department of Bacteriology and Immunology, Haartman Institute, Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland.
J Immunol. 2013 Aug 15;191(4):1775-84. doi: 10.4049/jimmunol.1300638. Epub 2013 Jul 17.
Staphylococcus aureus is a major human pathogen causing more than a tenth of all septicemia cases and often superficial and deep infections in various tissues. One of the immune evasion strategies of S. aureus is to secrete proteins that bind to the central complement opsonin C3b. One of these, extracellular complement binding protein (Ecb), is known to interfere directly with functions of C3b. Because C3b is also the target of the physiological plasma complement regulator, factor H (FH), we studied the effect of Ecb on the complement regulatory functions of FH. We show that Ecb enhances acquisition of FH from serum onto staphylococcal surfaces. Ecb and FH enhance mutual binding to C3b and also the function of each other in downregulating complement activation. Both Ecb and the C-terminal domains 19-20 of FH bind to the C3d part of C3b. We show that the mutual enhancing effect of Ecb and FH on binding to C3b depends on binding of the FH domain 19 to the C3d part of C3b next to the binding site of Ecb on C3d. Our results show that Ecb, FH, and C3b form a tripartite complex. Upon exposure of serum-sensitive Haemophilus influenzae to human serum, Ecb protected the bacteria, and this effect was enhanced by the addition of the C-terminal domains 19-20 of FH. This finding indicates that the tripartite complex formation could give additional protection to bacteria and that S. aureus is thereby able to use host FH and bacterial Ecb in a concerted action to eliminate C3b at the site of infection.
金黄色葡萄球菌是一种主要的人类病原体，可导致十分之一以上的败血症病例，并经常导致各种组织的浅表和深部感染。金黄色葡萄球菌的免疫逃避策略之一是分泌与中央补体调理素 C3b 结合的蛋白质。其中一种，细胞外补体结合蛋白（Ecb），已知可直接干扰 C3b 的功能。由于 C3b 也是生理血浆补体调节剂因子 H（FH）的靶标，因此我们研究了 Ecb 对 FH 的补体调节功能的影响。我们表明 Ecb 增强了从血清到葡萄球菌表面的 FH 摄取。Ecb 和 FH 增强了彼此与 C3b 的结合，并且彼此在下调补体激活方面的功能也增强。Ecb 和 FH 的 C 末端结构域 19-20 都与 C3b 的 C3d 部分结合。我们表明，Ecb 和 FH 相互增强与 C3b 的结合取决于 FH 结构域 19 与 Ecb 在 C3d 上的结合位点相邻的 C3d 部分的结合。我们的结果表明，Ecb、FH 和 C3b 形成了一个三分体复合物。当对人血清敏感的流感嗜血杆菌暴露于人血清中时，Ecb 保护了细菌，并且这种作用通过添加 FH 的 C 末端结构域 19-20 而增强。这一发现表明，三分体复合物的形成可以为细菌提供额外的保护，并且金黄色葡萄球菌因此能够利用宿主 FH 和细菌 Ecb 协同作用，在感染部位消除 C3b。
