Abstract
Mycobacterium abscessus pulmonary disease (Mab-PD) shows rising global incidence and low cure rates. Mab exhibits marked phenotypic heterogeneity, with infection outcomes likely dependent on strain-specific host interactions. Through in vivo morphotype switching, we obtained a rough strain (Mab-R) that showed higher virulence, bacterial loads, and lung pathology than the smooth morphotype. Transcriptomic analysis revealed that Mab-R adapts to macrophage functional states by modulating virulence and metabolic genes, promoting intracellular survival. Single-cell RNA sequencing uncovered dynamic macrophage reprogramming during infection. In acute infection, alveolar macrophages and C1qa+ interstitial macrophages cleared Mab-R via programmed cell death, while newly recruited monocytes showed strong phagocytic capacity but incomplete bacterial clearance. During chronic infection, enhanced T cell immunity and resident-like macrophage dominance facilitated inflammation resolution. These findings reveal host-pathogen interplay driving Mab-R persistence and identify bacterial metabolic adaptation and macrophage reprogramming as potential therapeutic targets for chronic Mab-PD.