Potent inhibition of macrophage responses to IFN-γ by live virulent Mycobacterium tuberculosis is independent of mature mycobacterial lipoproteins but dependent on TLR2
Potent inhibition of macrophage responses to IFN-γ by live virulent Mycobacterium tuberculosis is independent of mature mycobacterial lipoproteins but dependent on TLR2
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DOI：
10.4049/jimmunol.176.5.3019
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发表时间：
2006-03-01
影响因子：
4.4
通讯作者：
Ernst, Joel D.
中科院分区：
文献类型：
--
作者：
Banaiee, Niaz;Kincaid, Eleanor Z.;Ernst, Joel D.
结核分枝杆菌是一种非常成功的病原体，尽管有免疫反应，仍可以持续并引起疾病。抵抗消除的一种潜在机制是抑制IFN-gamma的作用。我们以前有。结果表明，活结核分枝杆菌抑制了对IFN-Gamma的选定巨噬细胞反应，并且纯化结核分枝杆菌19-KDA脂蛋白抑制了通过TLR2依赖性途径抑制所选IFN-GAMMA响应基因的诱导，而肽聚糖抑制了对肽聚糖对Ifn-Gamma的反应的响应。通过TLR2无关的途径。为了确定脂蛋白对抑制IFN-gamma反应的相对贡献，我们删除了编码脂蛋白信号肽酶的结核分枝杆菌基因（ISPA）。这表明结核分枝杆菌脂蛋白的加工对于刺激TLR2报告基细胞是必不可少的，但是LSPA突变体抑制对IFN-Gamma的巨噬细胞反应，其程度与野生型细菌相同。缺乏TLR2的巨噬细胞对结核分枝杆菌菌株对抑制更具抵抗力，这表明非脂蛋白TLR2激动剂有助于抑制。确实，我们发现结核分枝杆菌的磷脂酰磷酸糖醇曼南抑制了巨噬细胞对IFN-gamma的反应。 M. to骨抑制对IFN-GAMMA的反应需要新的蛋白质合成，这表明先天免疫刺激的晚期作用是抑制对IFN-GAMMA的反应。这些结果表明，结核分枝杆菌具有抑制对IFN-gamma反应的多种机制。
Mycobacterium tuberculosis is a highly successful pathogen that can persist and cause disease despite an immune response. One potential mechanism for resisting elimination is by inhibiting the action of IFN-gamma. We have previously. shown that live M. tuberculosis inhibits selected macrophage responses to IFN-gamma, and that purified M. tuberculosis 19-kDa lipoprotein inhibits induction of selected IFN-gamma-responsive genes through a TLR2-dependent pathway, whereas peptidoglycan inhibits responses to IFN-gamma by a TLR2-independent pathway. To determine the relative contribution of lipoproteins to the inhibition of responses to IFN-gamma, we deleted the M. tuberculosis gene (IspA) that encodes lipoprotein signal peptidase. This revealed that M. tuberculosis lipoprotein processing is indispensable for stimulation of TLR2 reporter cells, but that the lspA mutant inhibits macrophage responses to IFN-gamma to the same extent as wild-type bacteria. Macrophages lacking TLR2 are more resistant to inhibition by either strain of M. tuberculosis, suggesting that nonlipoprotein TLR2 agonists contribute to inhibition. Indeed, we found that phosphatidlylinositol mannan from M. tuberculosis inhibits macrophage responses to IFN-gamma. M.tuberculosis inhibition of responses to IFN-gamma requires new protein synthesis, indicating that a late effect of innate immune stimulation is the inhibition of responses to IFN-gamma. These results establish that M. tuberculosis possesses multiple mechanisms of inhibiting responses to IFN-gamma.