Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins
Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins
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DOI：
10.1182/blood-2008-04-153882
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发表时间：
2009-01-08
期刊：
影响因子：
20.3
通讯作者：
de Haas, Carla J. C.
中科院分区：
文献类型：
--
作者：
Bestebroer, Jovanka;van Kessel, Kok P. M.;de Haas, Carla J. C.
金黄色葡萄球菌分泌几种调节免疫应答的毒力因子。葡萄球菌超抗原样蛋白（SSL）是一个由14种外毒素组成的家族，与超抗原具有同源性，但功能尚不清楚。最近，我们发现SSL 5依赖于唾液酸刘易斯X与P-选择素糖蛋白配体1结合，并抑制P-选择素依赖的中性粒细胞滚动。在这里，我们表明，SSL 5有效和特异性抑制过敏毒素和所有类别的趋化因子的白细胞活化。SSL 5抑制钙动员，肌动蛋白聚合，趋化因子和过敏毒素诱导的趋化性，但不受其他化学引诱剂。抗体竞争实验表明，SSL 5靶向几种趋化因子和过敏毒素受体。此外，转染研究表明，SSL 5结合所有G蛋白偶联受体（GPCR）的糖基化N-末端，但仅抑制需要受体N-末端激活的蛋白质性质的刺激。此外，SSL 5通过其共同的糖胺聚糖结合位点增加趋化因子与细胞的结合，而不依赖于趋化因子受体。聚糖对于GPCR和趋化因子结合两者均显示出重要性。因此，SSL 5是金黄色葡萄球菌的一种重要的免疫调节蛋白，其靶向白细胞外渗的几个关键的初始阶段。因此，它是一种潜在的新化合物，用于与化学引诱物及其受体相关的疾病和以白细胞过度募集为特征的疾病。（血。2009;113：328-337）
Staphylococcus aureus secretes several virulence factors modulating immune responses. Staphylococcal superantigen-like (SSL) proteins are a family of 14 exotoxins with homology to superantigens, but with generally unknown function. Recently, we showed that SSL5 binds to P-selectin glycoprotein ligand 1 dependently of sialyl Lewis X and inhibits P-selectin-dependent neutrophil rolling. Here, we show that SSL5 potently and specifically inhibits leukocyte activation by anaphylatoxins and all classes of chemokines. SSL5 inhibited calcium mobilization, actin polymerization, and chemotaxis induced by chemokines and anaphylatoxins but not by other chemoattractants. Antibody competition experiments showed that SSL5 targets several chemokine and anaphylatoxin receptors. In addition, transfection studies showed that SSL5 binds glycosylated N-termini of all G protein-coupled receptors (GPCRs) but only inhibits stimuli of protein nature that require the receptor N-terminus for activation. Furthermore, SSL5 increased binding of chemokines to cells independent of chemokine receptors through their common glycosaminoglycan-binding site. Importance of glycans was shown for both GPCR and chemokine binding. Thus, SSL5 is an important immunomodulatory protein of S aureus that targets several crucial, initial stages of leukocyte extravasation. It is therefore a potential new antiinflammatory compound for diseases associated with chemoattractants and their receptors and disorders characterized by excessive recruitment of leukocytes. (Blood. 2009;113:328-337)