Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages.
Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages.
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DOI：
10.3389/fcimb.2015.00063
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发表时间：
2015
影响因子：
5.7
通讯作者：
Pham T
中科院分区：
文献类型：
--
作者：
Bermudez LE;Danelishvili L;Babrack L;Pham T
鸟分枝杆菌人源亚种（MAH）是一种感染免疫功能低下人群的环境细菌。MAH病例的发病率正在上升，因此了解与该细菌相关的致病机制至关重要。MAH感染巨噬细胞，几天后感染会引发吞噬细胞凋亡。许多细胞内的MAH会从发生凋亡的细胞中逃逸，从而感染邻近的巨噬细胞。我们在U937单核吞噬细胞中对MAH突变体的转座子库进行筛选，以找出无法从发生凋亡的巨噬细胞中逃逸的突变体。基因MAV_2235、MAV_2120、MAV_2410和MAV_4563发生突变会导致细菌在细胞凋亡时无法从巨噬细胞中逸出。对突变的互补可完全或部分纠正表型。与野生型细菌相比，对突变体在巨噬细胞中存活能力的测试表明，在感染长达4天的时间内，突变克隆的毒力并未减弱。然而，体内测试表明，与小鼠组织中的野生型MAC104相比，所有MAH克隆的毒力均减弱。尽管与细菌无法离开凋亡巨噬细胞相关的机制尚不清楚，但对MAH蛋白的巨噬细胞胞质靶点的鉴定表明，它们要么干扰蛋白质降解机制，要么干扰翻译后机制。将tatC鉴定为一种与MAH离开巨噬细胞的能力有关的MAH蛋白，表明分泌的效应物参与了这一过程。该研究揭示了一种从巨噬细胞逃逸的途径，这与结核分枝杆菌不同。
Mycobacterium avium subsp. hominissuis (MAH) is an environmental bacteria that infects immunocompromised humans. MAH cases are increasing in incidence, making it crucial to gain knowledge of the pathogenic mechanisms associated with the bacterium. MAH infects macrophages and after several days the infection triggers the phagocyte apoptosis. Many of the intracellular MAH escape the cell undergoing apoptosis leading to infection of neighboring macrophages. We screened a transposon bank of MAH mutants in U937 mononuclear phagocytes for the inability to escape macrophages undergoing apoptosis. Mutations in genes; MAV_2235, MAV_2120, MAV_2410, and MAV_4563 resulted in the inability of the bacteria to exit macrophages upon apoptosis. Complementation of the mutations corrected the phenotype either completely or partially. Testing for the ability of the mutants to survive in macrophages compared to the wild-type bacterium revealed that the mutant clones were not attenuated up to 4 days of infection. Testing in vivo, however, demonstrated that all the MAH clones were attenuated compared with the wild-type MAC 104 in tissues of mice. Although the mechanism associated with the bacterial inability to leave apoptotic macrophages is unknown, the identification of macrophage cytoplasm targets for the MAH proteins suggest that they interfere either with protein degradation machinery or post-translation mechanisms. The identification of tatC as a MAH protein involved in the ability of MAH to leave macrophages, suggests that secreted effector(s) are involved in the process. The study reveals a pathway of escape from macrophages, not shared with Mycobacterium tuberculosis.