Mycobacterium tuberculosis prevents inflammasome activation
Mycobacterium tuberculosis prevents inflammasome activation
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DOI：
10.1016/j.chom.2008.03.003
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发表时间：
2008-04-01
影响因子：
30.3
通讯作者：
Deretic, Vojo
中科院分区：
文献类型：
--
作者：
Master, Sharon S.;Rampini, Silvana K.;Deretic, Vojo
结核分枝杆菌（Mtb）寄生于宿主巨噬细胞并破坏宿主先天性和适应性免疫。由Mtb引起的几种细胞因子是分枝杆菌清除的介质或参与结核病病理学。令人惊讶的是，白细胞介素-1 β（IL-1 β），一种主要的促炎细胞因子，并没有涉及宿主-结核分枝杆菌的相互作用。IL-1 β通过炎性小体（一种专门的炎性半胱天冬酶活化蛋白复合物）组装后的加工而活化。在这里，我们表明Mtb阻止炎性小体激活和IL-1 β加工。Mtb基因，zmp 1，它编码一个假定的锌+金属蛋白酶，是需要这个过程。用zmp 1缺失的Mtb感染巨噬细胞触发炎性体的激活，导致IL-1 β分泌增加，含Mtb的吞噬体的成熟增强，巨噬细胞对分枝杆菌的清除改善，以及气溶胶感染小鼠肺中的细菌负荷降低。因此，我们揭示了IL-1 β在Mtb控制和分枝杆菌系统中的先前被掩盖的作用，该分枝杆菌系统防止炎性小体，因此防止IL-1 β活化。
Mycobacterium tuberculosis (Mtb) parasitizes host macrophages and subverts host innate and adaptive immunity. Several cytokines elicited by Mtb are mediators of mycobacterial clearance or are involved in tuberculosis pathology. Surprisingly, interleukin-1 beta (IL-1 beta), a major proinflammatory cytokine, has not been implicated in host-Mtb interactions. IL-1 beta is activated by processing upon assembly of the inflammasome, a specialized inflammatory caspase-activating protein complex. Here, we show that Mtb prevents inflammasome activation and IL-1 beta processing. An Mtb gene, zmp1, which encodes a putative Zn2+ metalloprotease, is required for this process. Infection of macrophages with zmp1-deleted Mtb triggered activation of the inflammasome, resulting in increased IL-1 beta secretion, enhanced maturation of Mtb containing phagosomes, improved mycobacterial clearance by macrophages, and lower bacterial burden in the lungs of aerosol-infected mice. Thus, we uncovered a previously masked role for IL-1 beta in the control of Mtb and a mycobacterial system that prevents inflammasome and, therefore, IL-1 beta activation.