Zheng Weihao, Chang I-Chang, Limberis Jason, Budzik Jonathan, Zha Beth Shoshana, Howard Zachary, Chen Lucas, Ernst Joel
University of California, San Francisco.
University of California.
Res Sq. 2023 Jun 15:rs.3.rs-3049913. doi: 10.21203/rs.3.rs-3049913/v1.
(Mtb) persists in lung myeloid cells during chronic infection. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, we determined that in chronic phase, CD11c monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb than alveolar macrophages (AM), neutrophils, and less permissive CD11c MNC2. Transcriptomic and functional studies of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1, which have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cells via its ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.
结核分枝杆菌（Mtb）在慢性感染期间在肺髓样细胞中持续存在。然而，Mtb逃避清除的机制尚未完全了解。在此，我们确定在慢性期，称为MNC1（单核细胞亚群1）的CD11c单核细胞衍生的肺细胞比肺泡巨噬细胞（AM）、中性粒细胞以及不那么容易被感染的CD11c MNC2含有更多存活的Mtb。对分选细胞的转录组学和功能研究表明，溶酶体生物发生途径在MNC1中表达不足，与AM相比，MNC1的溶酶体含量、酸化和蛋白水解活性较低，并且核内转录因子EB（TFEB）较少，TFEB是溶酶体生物发生的主要调节因子。Mtb感染不会导致MNC1中的溶酶体缺陷。相反，Mtb通过其ESX-1分泌系统将MNC1和MNC2募集到肺部，以便从AM传播到这些细胞。c-Abl酪氨酸激酶抑制剂尼洛替尼激活TFEB并增强体内原代巨噬细胞以及MNC1和MNC2的溶酶体功能，改善对Mtb感染的控制。我们的结果表明，Mtb利用溶酶体含量低的单核细胞衍生细胞在体内持续存在，这提示了宿主导向性结核病治疗的一个潜在靶点。
