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.

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中文翻译：

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酚糖脂促进分枝杆菌从杀菌组织驻留巨噬细胞中逃逸

结核分枝杆菌(Mtb) 通过沉积在肺泡中的气溶胶液滴进入宿主，细菌首先遇到肺泡巨噬细胞。我们研究了光学透明斑马鱼中最早的分枝杆菌-巨噬细胞相互作用。第一反应的常驻巨噬细胞吞噬并根除感染的分枝杆菌，这表明为了建立成功的感染，分枝杆菌必须从最初感染的常驻巨噬细胞逃逸到允许生长的单核细胞中。我们确定了分枝杆菌膜酚糖脂 (PGL) 在工程这一转变中的关键作用。PGL 激活常驻巨噬细胞中的 STING 胞质传感通路，诱导趋化因子 CCL2 的产生，进而招募循环 CCR2 ⁺单核细胞进行感染。^{受感染的巨噬细胞与CCR2 +}单核细胞的短暂融合使得细菌转移和随后的传播，并且中断这种转移以延长分枝杆菌在常驻巨噬细胞中的逗留，从而促进感染的清除。人类肺泡巨噬细胞在感染后以 PGL 依赖性方式产生 CCL2，这证明了 PGL 阻断干预措施或 PGL 靶向疫苗策略在预防结核病方面的潜力。

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