ISCIENCE

Mycobacterium tuberculosis (Mtb), is the main pathogen causing tuberculosis (TB). Autophagy is an important regulatory pathway to eliminate intracellular Mtb. However, how Mtb escapes autophagy clearance remains largely unclear. Here, we found that microRNA-25 (miR-25) expression was significantly upregulated in the lung tissues of mice infected with Bacillus Calmette-Guerin (BCG) and macrophages infected with Mtb or BCG, especially in the early stages of infection. MiR-25 can significantly increase the survival of Mtb and BCG in macrophages. We validated that miR-25 targets the NPC1 protein located on the lysosomal membrane, resulting in damage to lysosomal function, thereby inhibiting autophagolysosome formation and promoting the survival of Mtb and BCG. Consistently, mice lacking miR-25 exhibited more resistant to BCG infection. In addition, we found that Rv1759c induces the expression of miR-25 through NFKB inhibitor zeta (NFKBIZ). Together, we reveal a new mechanism by which Mtb regulates NPC1 to influence lysosomal function and increase the survival of Mtb through the autophagy pathway, providing an early biomarker for TB infection and a new treatment strategy against TB.

结核分枝杆菌（Mycobacterium tuberculosis，简称Mtb）是引发肺结核（TB）的主要病原体。自噬是清除细胞内Mtb的重要调控途径。然而，Mtb如何逃避免疫清除机制仍鲜有明确。在本研究中，我们发现感染卡介苗（Bacillus Calmette-Guerin，简称BCG）的小鼠肺组织和感染Mtb或BCG的巨噬细胞中microRNA-25（miR-25）的表达显著上调，尤其是在感染早期。miR-25能够显著提高Mtb和BCG在巨噬细胞中的存活率。我们验证了miR-25靶向位于溶酶体膜上的NPC1蛋白，导致溶酶体功能受损，从而抑制自噬溶酶体形成，促进Mtb和BCG的存活。一致地，缺乏miR-25的小鼠对BCG感染表现出更强的抵抗力。此外，我们发现Rv1759c通过NFKB抑制剂ζ（NFKBIZ）诱导miR-25的表达。综合以上，我们揭示了一种新的机制，即Mtb通过调控NPC1影响溶酶体功能，进而通过自噬途径增加Mtb的存活率，这为TB感染的早期生物标志物和针对TB的新治疗策略提供了理论依据。