Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane
Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane
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DOI：
10.1111/j.1462-5822.2006.00758.x
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发表时间：
2006-12-01
影响因子：
3.4
通讯作者：
Descoteaux, Albert
中科院分区：
文献类型：
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作者：
Lodge, Robert;Diallo, Tamsir O.;Descoteaux, Albert
杜氏利什曼原虫前鞭毛体的吞噬作用以表面糖脂磷脂多糖(LPG)介导的吞噬溶酶体生物生成抑制为特征。然而，这种抑制巨噬细胞功能的后果仍有待确定。在本研究中，我们研究了LPG介导的吞噬小体重塑对NADPH氧化酶复合体组装和功能的影响。野生型和LPG缺陷的杜诺氏乳杆菌前鞭毛体的吞噬作用触发了类似水平的超氧化物的释放。然而，野生型前鞭毛体，而不是LPG缺陷突变体，抑制了吞噬小体超氧化物的产生。共聚焦显微镜成像显示，膜组分gp91(Phox)和Rho家族GTPase rac1存在于含有野生型或LPG缺陷前鞭毛体的吞噬小体上。相反，NADPH氧化酶胞浆组分P47(Phox)和P67(Phox)以依赖LPG的方式被排除在吞噬小体之外。这种抑制并不是NADPH氧化酶激活过程启动过程中普遍缺陷的结果，因为野生型和LPG缺陷的前鞭毛体都诱导了p47(Phox)的磷酸化和含有p47(Phox)和p67(Phox)的复合体的形成。因此，通过重建其细胞内栖息地，杜诺瓦尼乳杆菌前鞭毛体阻止了功能性吞噬体型NADPH氧化酶复合体的组装，从而逃避了一种重要的宿主天然防御机制。
Phagocytosis of Leishmania donovani promastigotes is characterized by an inhibition of phagolysosome biogenesis mediated by the surface glycolipid lipophosphoglycan (LPG). However, the consequences of this inhibition on macrophage function remain to be determined. In this study, we investigated the impact of LPG-mediated phagosome remodelling on the assembly and function of the NADPH oxidase complex. Phagocytosis of both wild-type and LPGdefective L. donovani promastigotes triggered the release of similar levels of superoxide. However, wildtype promastigotes, but not LPG-defective mutants, inhibited generation of superoxide at the phagosome. Confocal microscopy imaging revealed that the membrane component gp91(phox) and the Rho-family GTPase Rac1 were present on phagosomes containing either wild- type or LPG-defective promastigotes. In contrast, the NADPH oxidase cytosolic components p47(phox) and p67(phox) were excluded from phagosomes in a LPG-dependent fashion. This inhibition is not the consequence of a general defect in the initiation of the NADPH oxidase activation process because both wild-type and LPG-defective promastigotes induced p47(phox) phosphorylation and the formation of complexes containing p47(phox) and p67(phox). Thus, by remodelling their intracellular habitat, L. donovani promastigotes prevent the assembly of a functional phagosomal NADPH oxidase complex, thereby evading an important host innate defence mechanism.