Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages.
Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages.
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DOI：
10.1016/j.immuni.2017.08.003
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发表时间：
2017-09-19
期刊：
影响因子：
32.4
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Cambier CJ;O'Leary SM;O'Sullivan MP;Keane J;Ramakrishnan L
结核分枝杆菌（Mtb）通过沉积在肺泡中的气溶胶飞沫进入宿主，在肺泡中细菌首先遇到肺内肺泡巨噬细胞。我们在光学透明的斑马鱼中研究了最早的分枝杆菌-巨噬细胞相互作用。首先反应的常驻巨噬细胞吞噬并根除了感染的分枝杆菌，这表明要建立成功的感染，分枝杆菌必须从最初被感染的常驻巨噬细胞逃到允许生长的单核细胞中。我们确定了分枝杆菌膜酚醛糖脂（PGL）在工程转化中的关键作用。PGL激活了巨噬细胞中的STING细胞质感应途径，诱导趋化因子CCL2的产生，进而募集循环CCR2+单核细胞感染。感染的巨噬细胞与CCR2+单核细胞的短暂融合使细菌转移和随后的传播，中断这种转移以延长分枝杆菌在常驻巨噬细胞中的停留，促进了感染的清除。人类肺泡巨噬细胞在感染后以pgl依赖的方式产生CCL2，这表明pgl阻断干预或pgl靶向疫苗策略在预防结核病中的潜力。分枝杆菌酚类糖脂通过STING激活诱导巨噬细胞CCL2， CCL2将允许分枝杆菌的单核细胞招募到组织巨噬细胞中。分枝杆菌通过细胞融合事件从组织巨噬细胞转移到单核细胞。Cambier等人发现，分枝杆菌表面脂质PGL激活肺内常驻杀微生物巨噬细胞的STING通路，使细菌通过通过CCL2-CCR2趋化因子轴诱导允许分枝杆菌的单核细胞募集。他们的发现揭示了一种使分枝杆菌传播的重新定位策略，并论证了针对PGL的干预措施在预防结核病中的潜力。
Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2+ monocytes toward infection. Transient fusion of infected macrophages with CCR2+ monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 in a PGL-dependent fashion following infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis. Microbicidal tissue-resident macrophages are first responders to mycobacteria Mycobacterial phenolic glycolipid induces macrophage CCL2 through STING activation CCL2 recruits mycobacterium-permissive monocytes to the tissue-resident macrophage Mycobacteria transfer from tissue macrophage to monocyte through a cell fusion event Cambier et al. find that activation of the STING pathway in lung-resident microbicidal macrophages by the mycobacterial surface lipid PGL enables bacterial escape by inducing the recruitment of mycobacterium-permissive monocytes via the CCL2-CCR2 chemokine axis. Their findings reveal a relocation strategy that enables mycobacterial dissemination, and argue for the potential of interventions targeting PGL in the prevention of tuberculosis.
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影响因子：
11.2
作者：
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影响因子：
30.3
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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