Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes
Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes
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DOI：
10.4049/jimmunol.1202900
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Nisini, Roberto
中科院分区：
文献类型：
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作者：
Mariotti, Sabrina;Pardini, Manuela;Nisini, Roberto
休眠被定义为结核分枝杆菌的稳定但可逆的非复制状态。目前认为休眠的M。结核病（D-Mtb）是潜伏性结核病（TB）感染的原因。最近，D-Mtb也在活动性TB患者的粪便中显示，但D-Mtb刺激特异性免疫应答的能力尚未研究。我们观察到，当巨噬细胞感染D-Mtb而不是复制M时，纯化的蛋白衍生物特异性人CD 4（+）T淋巴细胞更有效地识别分枝杆菌Ag。结核病（R-Mtb）。即使当两种形式的分枝杆菌同等地感染和刺激巨噬细胞时，也会发生不同的Ag识别，巨噬细胞分泌相同的细胞因子模式并以相同的水平表达MHC I类和II类分子。然而，在巨噬细胞中，D-Mtb而不是R-Mtb与成熟的吞噬溶酶体标记物LAMP-1和空泡质子ATP酶共定位。与R-Mtb不同，D-Mtb不能干扰吞噬体pH并且不抑制巨噬细胞的蛋白水解效率。我们发现，D-Mtb下调基因Rv 3875编码ESAT-6，这是所需的R-Mtb阻断吞噬体成熟与Rv 3310基因产物SapM，以前被证明是下调D-Mtb。因此，我们的研究结果表明，D-Mtb不能逃脱MHC II类Ag加工途径，因为它缺乏阻断吞噬体成熟所需的基因的表达。数据表明，转入休眠状态不仅代表了潜伏性结核感染的一种生存机制，也是结核分枝杆菌的一种新的生存机制。调节结核病不同阶段免疫反应的结核病策略。
Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative-specific human CD4(+) T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB.