Master Sharon S, Rampini Silvana K, Davis Alexander S, Keller Christine, Ehlers Stefan, Springer Burkhard, Timmins Graham S, Sander Peter, Deretic Vojo
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Cell Host Microbe. 2008 Apr 17;3(4):224-32. doi: 10.1016/j.chom.2008.03.003.
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-1beta (IL-1beta), a major proinflammatory cytokine, has not been implicated in host-Mtb interactions. IL-1beta 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-1beta processing. An Mtb gene, zmp1, which encodes a putative Zn(2+) metalloprotease, is required for this process. Infection of macrophages with zmp1-deleted Mtb triggered activation of the inflammasome, resulting in increased IL-1beta 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-1beta in the control of Mtb and a mycobacterial system that prevents inflammasome and, therefore, IL-1beta activation.
结核分枝杆菌（Mtb）寄生于宿主巨噬细胞中，并破坏宿主的固有免疫和适应性免疫。Mtb引发的多种细胞因子是分枝杆菌清除的介质，或参与结核病的病理过程。令人惊讶的是，主要促炎细胞因子白细胞介素-1β（IL-1β）尚未被证明参与宿主与Mtb的相互作用。IL-1β通过炎症小体（一种特殊的炎症半胱天冬酶激活蛋白复合物）组装时的加工而被激活。在此，我们表明Mtb可阻止炎症小体激活和IL-1β加工。此过程需要Mtb的一个基因zmp1，该基因编码一种假定的Zn(2+)金属蛋白酶。用缺失zmp1的Mtb感染巨噬细胞会触发炎症小体激活，导致IL-1β分泌增加、含吞噬体的Mtb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部细菌载量降低。因此，我们发现了IL-1β在控制Mtb方面以前未被发现的作用，以及一种阻止炎症小体进而阻止IL-1β激活的分枝杆菌系统。
