A mechanism of virulence:: Virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis
A mechanism of virulence:: Virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis
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DOI：
10.4049/jimmunol.176.6.3707
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发表时间：
2006-03-15
影响因子：
4.4
通讯作者：
Remold, Heinz G.
中科院分区：
文献类型：
--
作者：
Chen, Minjian;Gan, Huixian;Remold, Heinz G.
在低感染复数下，用结核分枝杆菌感染人单核细胞衍生的巨噬细胞，在感染后48 - 72小时会导致细胞死亡，具有凋亡或坏死的特征。主要诱导一种还是另一种细胞死亡方式取决于减毒株和强毒株所引起的线粒体膜扰动的差异。用减毒的H37Ra或强毒的H37Rv感染巨噬细胞会导致线粒体外膜通透性增加，其特征是细胞色素c从线粒体膜间隙释放以及细胞凋亡。线粒体外膜通透性增加是暂时的，在感染后6小时达到峰值，并且需要钙离子流以及B细胞慢性淋巴细胞白血病/淋巴瘤2相关蛋白X易位到线粒体中。相比之下，只有强毒的H37Rv会诱导由线粒体通透性转换引起的显著的线粒体跨膜电位（ΔΨm）丧失。ΔΨm的耗散也在感染后6小时达到峰值，是暂时的，可被经典的线粒体通透性转换抑制剂环孢菌素A抑制，需要线粒体钙离子负载，并且与B细胞慢性淋巴细胞白血病/淋巴瘤易位到线粒体无关。感染后6小时的暂时耗散对于结核分枝杆菌诱导巨噬细胞坏死至关重要，这是一种允许病原体进一步传播和疾病发展的机制。
Infection of human monocyte-derived macrophages with Mycobacterium tuberculosis at low multiplicities of infection leads 48-72 h after the infection to cell death with the characteristics of apoptosis or necrosis. Predominant induction of one or the other cell death modality depends on differences in mitochondrial membrane perturbation induced by attenuated and virulent strains. Infection of macrophages with the attenuated H37Ra or the virulent H37Rv causes mitochondrial outer membrane permeabilization characterized by cytochrome c release from the mitochondrial intermembrane space and apoptosis. Mitochondrial outer membrane permeabilization is transient, peaks 6 h after infection, and requires Ca2+ flux and B cell chronic lymphocytic leukemia/lymphoma 2-associated protein X translocation into mitochondria. In contrast, only the virulent H37Rv induces significant mitochondrial transmembrane potential (Delta psi(m)) loss caused by mitochondrial permeability transition. Dissipation of Delta psi(m) also peaks at 6 h after infection, is transient, is inhibited by the classical mitochondrial permeability transition inhibitor cyclosporine A, has a requirement for mitochondrial Ca2+ loading, and is independent of B cell chronic lymphocytic leukemia/lymphoma translocation into the mitochondria. Transient dissipation of 6 h after infection is essential for the induction of macrophage necrosis by Mtb, a mechanism that allows further dissemination of the pathogen and development of the disease.