HDAC6 contributes to human resistance against Mycobacterium tuberculosis infection via mediating innate immune responses
HDAC6 contributes to human resistance against Mycobacterium tuberculosis infection via mediating innate immune responses
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DOI：
10.1096/fj.202100614r
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Fuzhen Zhang;Shanshan Yu;Qiyao Chai;Jing Wang;Tuoya Wu;Rongmei Liu;Yi Liu;C. Liu;Y. Pang
中科院分区：
文献类型：
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作者：
Fuzhen Zhang;Shanshan Yu;Qiyao Chai;Jing Wang;Tuoya Wu;Rongmei Liu;Yi Liu;C. Liu;Y. Pang
由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）仍然是世界范围内发病率和死亡率的主要原因。越来越多的证据表明，某些被称为耐药者的个体对结核病感染具有天然耐药性。抵抗者表型与宿主有效的先天免疫应答有关，但其潜在机制和关键免疫因素仍不清楚。在这里，我们发现在Mtb感染后，来自TB抵抗者的单核细胞衍生的巨噬细胞（MDM）表现出明显更高的TNF-α、IL-1β和IL-6的产生，更高的酸性空泡中的细菌比例，以及更低的细胞内细菌负荷，与健康对照、潜伏性TB感染个体和TB患者相比。来自耐药者的巨噬细胞的这种增强的抗Mtb免疫能力在很大程度上取决于组蛋白脱乙酰酶6（HDAC 6），其表达在Mtb感染期间特异性地维持在来自TB耐药者的MDM中。此外，我们证明HDAC 6是巨噬细胞中含Mtb吞噬体酸化所必需的，从而控制Mtb的细胞内存活。总之，这些发现揭示了HDAC 6在人类对结核分枝杆菌感染的先天性抗性中不可或缺的作用，表明HDAC 6可以作为个体TB风险的标志物以及新的宿主定向抗TB治疗靶点。
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a major cause of morbidity and mortality worldwide. Increasing lines of evidence indicate that certain individuals, which are termed resisters, are naturally resistant to TB infection. The resister phenotype has been linked to host efficient innate immune responses, but the underlying mechanisms and the key immune factors remain unclear. Here, we find that upon Mtb infection, monocyte‐derived macrophages (MDMs) from TB resisters exhibited distinctly higher production of TNF‐α, IL‐1β and IL‐6, higher ratio of bacteria in acidic vacuoles, and lower intracellular bacterial loads, as compared to that from the healthy controls, individuals with latent TB infection, and TB patients. Such enhanced anti‐Mtb immune capacity of macrophages from resisters largely depends on histone deacetylase 6 (HDAC6), whose expression is specifically maintained in MDMs from TB resisters during Mtb infection. Furthermore, we demonstrate that HDAC6 is required for acidification of Mtb‐containing phagosomes in macrophages, thus controlling the intracellular survival of Mtb. Taken together, these findings unravel an indispensable role of HDAC6 in human innate resistance against Mtb infection, suggesting that HDAC6 may serve as a marker for individual TB risk as well as a novel host‐directed anti‐TB therapeutic target.