Mononuclear cell dynamics in M. tuberculosis infection provide opportunities for therapeutic intervention.
Mononuclear cell dynamics in M. tuberculosis infection provide opportunities for therapeutic intervention.
复制标题
结核分枝杆菌感染中的单核细胞动力学为治疗干预提供了机会。
DOI：
10.1371/journal.ppat.1007154
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Ernst JD
中科院分区：
文献类型：
--
作者：
Norris BA;Ernst JD
结核分枝杆菌引起单核吞噬细胞的慢性感染，特别是常驻（肺泡）巨噬细胞、募集的巨噬细胞和树突状细胞。尽管这些细胞在结核病 (TB) 发病机制和免疫中很重要，但人们对这些细胞在感染部位的群体动态知之甚少。我们结合使用同源单核细胞过继转移和 DNA 脉冲追踪标记，以确定小鼠结核分枝杆菌感染的慢性适应性免疫阶段单核吞噬细胞的运输、分化和感染的动力学和特征。我们发现 Ly6Chi 单核细胞快速运输到肺部，其中一个亚群变成 Ly6Clo 并保留在肺血管空间中，而其余的则迁移到肺实质中并分化为 Ly6Chi 树突状细胞、CD11b+ 树突状细胞和招募的巨噬细胞。与患有结核病的人类一样，感染结核分枝杆菌的小鼠的血液单核细胞数量有所增加；这是由于从骨髓的排出增加，而不是从血液的排出延迟。分裂细胞的脉冲追踪标记和流式细胞仪分析显示，Ly6Chi 单核细胞的 T1/2 约为 15 小时，表明它们在进入受感染肺部实质后迅速分化；相比之下，从 Ly6Chi 单核细胞分化而来的细胞更新速度较慢，但频率会在不到一周的时间内减少。新细胞（通过脉冲追踪标记识别）在肺部出现后 1-3 天内获得细菌，这表明细菌经常遇到新的细胞生态位，即使在慢性感染阶段也是如此。我们的研究结果表明，结核分枝杆菌感染部位的单核吞噬细胞群是高度动态的，这为针对单核细胞的宿主定向治疗的特定方法提供了支持，包括训练免疫，作为结核病的潜在干预措施，通过用新招募的细胞取代抗分枝杆菌能力有限的细胞，能够更好地限制和杀死结核分枝杆菌。在某些慢性感染（例如结核病）期间，包括巨噬细胞和树突状细胞在内的炎症细胞被募集到受感染的组织中，并在那里聚集形成称为肉芽肿的组织病变。尽管肉芽肿可以长期存在，但构成肉芽肿的细胞群的动态尚不清楚。我们使用多种方法发现，在小鼠慢性感染结核分枝杆菌的过程中，单核细胞、巨噬细胞和树突状细胞群是高度动态的：最近增殖的细胞迅速迁移到受感染的肺组织，但它们的半衰期持续不到一周。我们还发现，最近增殖的细胞在到达肺部一天后就会被结核分枝杆菌感染，这表明细菌经常移动到新的细胞生态位，即使在慢性感染阶段也是如此。遇到结核分枝杆菌的细胞群的动态性质表明，通过用抗分枝杆菌活性增强的细胞替换抗分枝杆菌活性较差的细胞，训练免疫等干预措施具有潜在的治疗作用。这些干预措施可以改善耐药结核病的治疗结果。
Mycobacterium tuberculosis causes chronic infection of mononuclear phagocytes, especially resident (alveolar) macrophages, recruited macrophages, and dendritic cells. Despite the importance of these cells in tuberculosis (TB) pathogenesis and immunity, little is known about the population dynamics of these cells at the sites of infection. We used a combination of congenic monocyte adoptive transfer, and pulse-chase labeling of DNA, to determine the kinetics and characteristics of trafficking, differentiation, and infection of mononuclear phagocytes during the chronic, adaptive immune phase of M. tuberculosis infection in mice. We found that Ly6Chi monocytes traffic rapidly to the lungs, where a subpopulation become Ly6Clo and remain in the lung vascular space, while the remainder migrate into the lung parenchyma and differentiate into Ly6Chi dendritic cells, CD11b+ dendritic cells, and recruited macrophages. As in humans with TB, M. tuberculosis-infected mice have increased numbers of blood monocytes; this is due to increased egress from the bone marrow, and not delayed egress from the blood. Pulse-chase labeling of dividing cells and flow cytometry analysis revealed a T1/2 of ~15 hrs for Ly6Chi monocytes, indicating that they differentiate rapidly upon entry to the parenchyma of infected lungs; in contrast, cells that differentiate from Ly6Chi monocytes turn over more slowly, but diminish in frequency in less than one week. New cells (identified by pulse-chase labeling) acquire bacteria within 1–3 days of appearance in the lungs, indicating that bacteria regularly encounter new cellular niches, even during the chronic stage of infection. Our findings that mononuclear phagocyte populations at the site of M. tuberculosis infection are highly dynamic provide support for specific approaches for host-directed therapies directed at monocytes, including trained immunity, as potential interventions in TB, by replacing cells with limited antimycobacterial capabilities with newly-recruited cells better able to restrict and kill M. tuberculosis. During certain chronic infections such as tuberculosis, inflammatory cells, including macrophages and dendritic cells, are recruited to infected tissues where they aggregate to form tissue lesions known as granulomas. Although granulomas can persist long term, the dynamics of the cell populations that comprise granulomas are not well understood. We used a combination of methods to discover that, during chronic infection of mice with Mycobacterium tuberculosis, the monocyte, macrophage, and dendritic cell populations are highly dynamic: recently-proliferated cells traffic rapidly to infected lung tissues, yet they persist with a half-life of less than one week. We also found that recently-proliferated cells become infected with M. tuberculosis as soon as one day after their arrival in the lungs, indicating that the bacteria are regularly moving to new cellular niches, even during the chronic stage of infection. The dynamic nature of the cell populations that encounter M. tuberculosis suggests that interventions such as trained immunity have potential therapeutic roles, by replacing cells that have poor antimycobacterial activity with cells with enhanced antimycobacterial activity. These interventions could improve the outcomes of treatment of drug resistant tuberculosis.
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DOI：
10.1093/infdis/jit494
发表时间：
2014-02-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Naranbhai V;Hill AV;Abdool Karim SS;Naidoo K;Abdool Karim Q;Warimwe GM;McShane H;Fletcher H
通讯作者：
Fletcher H
影响因子：
7.3
作者：
Becker M;Güttler S;Bachem A;Hartung E;Mora A;Jäkel A;Hutloff A;Henn V;Mages HW;Gurka S;Kroczek RA
通讯作者：
Kroczek RA
影响因子：
15.9
作者：
Antonelli, Lis R. V.;Rothfuchs, Antonio Gigliotti;Sher, Alan
通讯作者：
Sher, Alan
影响因子：
3.1
作者：
Chackerian, AA;Alt, JM;Behar, SM
通讯作者：
Behar, SM
影响因子：
32.4
作者：
Cambier CJ;O'Leary SM;O'Sullivan MP;Keane J;Ramakrishnan L
通讯作者：
Ramakrishnan L