Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN
Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN
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DOI：
10.1128/iai.01256-08
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发表时间：
2009-10-01
影响因子：
3.1
通讯作者：
Appelmelk, Ben J.
中科院分区：
文献类型：
--
作者：
Driessen, Nicole N.;Ummels, Roy;Appelmelk, Ben J.
C 型凝集素树突状细胞 (DC) 特异性细胞间粘附分子 3 抓取非整联蛋白 (DC-SIGN) 是 DC 上结核分枝杆菌复合体分枝杆菌的主要受体。最近，我们发现，虽然分枝杆菌表面糖脂脂阿拉伯甘露聚糖 (ManLAM) 的甘露糖帽对于与 DC-SIGN 的结合至关重要，但这些帽的基因去除并没有减弱整个分枝杆菌与 DC-SIGN 和 DC 的相互作用。在这里，我们研究了结构相关的糖脂磷脂酰肌醇甘露糖苷 (PIM) 作为 DC-SIGN 可能配体的作用。在合成和天然 PIM 的结合测定中，DC-SIGN 对六甘露糖基化 PIM6 表现出高亲和力，六甘露糖基化 PIM6 包含与 ManLAM 上的甘露糖帽相同的末端 α(1 -> 2) 连接甘露糖基残基，但对二甘露糖基化 PIM2 和四甘露糖基化 PIM4 则分别没有。为了确定 PIM6 在整个分枝杆菌与 DC-SIGN 结合中的作用，创建了 PIM6 产生缺陷的牛分枝杆菌卡介苗突变菌株 (Delta pimE)，以及 PIM6 和 LAM 上甘露糖帽产生缺陷的双敲除菌株 (Delta pimE Delta capA)。与野生型菌株相比，两种突变菌株与 DC-SIGN 和 DC 的结合效果相似。此外，当用于刺激 DC 时，野生型和突变株诱导出相当水平的白细胞介素 10 和白细胞介素 12p40。因此，我们得出的结论是，像 ManLAM 一样，PIM6 代表真正的 DC-SIGN 配体，但其他未知的配体在分枝杆菌和 DC 之间的相互作用中占主导地位。
The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM6, which contains terminal alpha(1 -> 2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM2 and PIM4, respectively. To determine the role of PIM6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guerin deficient in the production of PIM6 (Delta pimE) was created, as well as a double knockout deficient in the production of both PIM6 and the mannose caps on LAM (Delta pimE Delta capA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.