ATG7 in innate immune cells is required for host defense against nontuberculous mycobacterial pulmonary infections

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.