Ramsland Paul A, Willoughby Natasha, Trist Halina M, Farrugia William, Hogarth P Mark, Fraser John D, Wines Bruce D
The Inflammatory Disease and Structural Immunology Laboratories, The Burnet Institute, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia.
Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15051-6. doi: 10.1073/pnas.0706028104. Epub 2007 Sep 11.
Infection by Staphylococcus aureus can result in severe conditions such as septicemia, toxic shock, pneumonia, and endocarditis with antibiotic resistance and persistent nasal carriage in normal individuals being key drivers of the medical impact of this virulent pathogen. In both virulent infection and nasal colonization, S. aureus encounters the host immune system and produces a wide array of factors that frustrate host immunity. One in particular, the prototypical staphylococcal superantigen-like protein SSL7, potently binds IgA and C5, thereby inhibiting immune responses dependent on these major immune mediators. We report here the three-dimensional structure of the complex of SSL7 with Fc of human IgA1 at 3.2 A resolution. Two SSL7 molecules interact with the Fc (one per heavy chain) primarily at the junction between the Calpha2 and Calpha3 domains. The binding site on each IgA chain is extensive, with SSL7 shielding most of the lateral surface of the Calpha3 domain. However, the SSL7 molecules are positioned such that they should allow binding to secretory IgA. The key IgA residues interacting with SSL7 are also bound by the leukocyte IgA receptor, FcalphaRI (CD89), thereby explaining how SSL7 potently inhibits IgA-dependent cellular effector functions mediated by FcalphaRI, such as phagocytosis, degranulation, and respiratory burst. Thus, the ability of S. aureus to subvert IgA-mediated immunity is likely to facilitate survival in mucosal environments such as the nasal passage and may contribute to systemic infections.
金黄色葡萄球菌感染可导致严重病症，如败血症、中毒性休克、肺炎和心内膜炎，而抗生素耐药性以及正常个体中持续的鼻腔携带是这种致病性病原菌产生医学影响的关键驱动因素。在致病性感染和鼻腔定植过程中，金黄色葡萄球菌都会遇到宿主免疫系统，并产生多种阻碍宿主免疫的因子。其中一种典型的葡萄球菌超抗原样蛋白SSL7，能有效结合IgA和C5，从而抑制依赖于这些主要免疫介质的免疫反应。我们在此报告了SSL7与人IgA1的Fc形成的复合物在3.2埃分辨率下的三维结构。两个SSL7分子主要在Cα2和Cα3结构域之间的连接处与Fc相互作用（每条重链一个）。每条IgA链上的结合位点很广泛，SSL7覆盖了Cα3结构域的大部分侧面。然而，SSL7分子的定位方式应使其能够与分泌型IgA结合。与SSL7相互作用的关键IgA残基也被白细胞IgA受体FcalphaRI（CD89）结合，从而解释了SSL7如何有效抑制由FcalphaRI介导的IgA依赖性细胞效应功能，如吞噬作用、脱颗粒和呼吸爆发。因此，金黄色葡萄球菌破坏IgA介导免疫的能力可能有助于其在鼻腔等黏膜环境中存活，并可能导致全身感染。
