Jeon Sang Min, Lee Yeon Ju, Lee Sang-Hee, Kim Soo In, Lee Bomi, Roh Taylor, Kim Young Jae, Kim Hyeon Ji, Kim In Soo, Whang Jake, Kim So-Young, Jhun Byung Woo, Chung Chaeuk, Kang Da Hyun, Yeo Min-Kyung, Kim Jin-Man, Jang Jichan, Min Jung-Joon, Komatsu Masaaki, Kim Jin Kyung, Park Woong-Yang, Jo Eun-Kyeong
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
Nat Commun. 2025 Jul 29;16(1):6966. doi: 10.1038/s41467-025-61791-1.
Infections caused by nontuberculous mycobacteria, such as Mycobacterium avium and Mycobacteroides abscessus, are becoming increasingly prevalent, and rising antibiotic resistance poses a significant clinical challenge. However, the mechanisms by which the host defense system controls these infections remain poorly understood. Here we show that the autophagy-related protein ATG7 in innate immune cells plays an essential role in controlling nontuberculous mycobacterial infection and protecting lung tissue from pathological inflammation. Patients with nontuberculous mycobacterial pulmonary disease exhibit reduced ATG7 expression in blood mononuclear cells and decreased ATG7 levels in necrotic lesions at disease sites. Mice lacking Atg7 in innate immune cells display elevated bacterial loads, excessive inflammation, mitochondrial damage, and multiple forms of cell death in the lungs, including pyroptosis, necrosis, and apoptosis. Notably, neutrophil infiltration in the lungs of these mice plays a key role in driving exacerbated inflammation and gasdermin E-associated cell death, which precede bacterial overgrowth. In vitro, Atg7-deficient macrophages exhibit impaired antimicrobial responses and reduced phagolysosomal fusion, but only modest increases in inflammation and cell death. These findings underscore the critical role of ATG7 in innate immune cells in orchestrating an effective host defense against nontuberculous mycobacterial lung infection by mitigating neutrophil-driven pathological inflammation and associated cell death.
由非结核分枝杆菌引起的感染，如鸟分枝杆菌和脓肿分枝杆菌，正变得越来越普遍，而不断上升的抗生素耐药性构成了重大的临床挑战。然而，宿主防御系统控制这些感染的机制仍知之甚少。在这里，我们表明先天免疫细胞中的自噬相关蛋白ATG7在控制非结核分枝杆菌感染和保护肺组织免受病理性炎症方面起着至关重要的作用。非结核分枝杆菌肺病患者的血液单核细胞中ATG7表达降低，疾病部位坏死病变中的ATG7水平也降低。先天免疫细胞中缺乏Atg7的小鼠肺部细菌载量升高、炎症过度、线粒体损伤以及多种形式的细胞死亡，包括焦亡、坏死和凋亡。值得注意的是，这些小鼠肺部的中性粒细胞浸润在加剧炎症和驱动与gasdermin E相关的细胞死亡中起关键作用，而这先于细菌过度生长。在体外，缺乏Atg7的巨噬细胞表现出抗菌反应受损和吞噬溶酶体融合减少，但炎症和细胞死亡仅适度增加。这些发现强调了ATG7在先天免疫细胞中通过减轻中性粒细胞驱动的病理性炎症和相关细胞死亡来协调宿主对非结核分枝杆菌肺部感染的有效防御中的关键作用。
