MAB_0676c-induced enhanced IL-10 production inhibits the autophagic flux via the MTOR/RUBCN pathway.

Mycobacterium abscessus subsp. abscessus (M.abs) is a nontuberculous mycobacterium that can infect human lung macrophages, which poses a public health concern. Understanding its mechanism is crucial for developing strategies to combat M.abs infections. M.abs survives within host cells by inhibiting autophagy, a defense mechanism used against intracellular pathogens; therefore, we investigated the mechanism underlying autophagy inhibition and human lung macrophage infection by M.abs. This study focuses on the M.abs UC22 strain, which exhibits stronger inhibition of autophagic flux compared to the M.abs ATCC 19,977 strain. Central to this study is MAB_0676c, a protein secreted by M.abs UC22, and its effects on autophagic flux and the innate immune response, particularly its role in enhancing IL-10 production, a known autophagy regulator. Experiments showed that MAB_0676c expression stabilizes autophagy-related proteins while reducing LC3-LAMP2 co-localization in macrophages, thereby inhibiting autophagy and promoting bacterial growth. Furthermore, blocking IL-10 reduced both autophagy-related protein levels and the intracellular growth of MAB_0676c-expressing bacteria. Therefore, M.abs UC22 mediates intracellular survival by inhibiting autophagy through IL-10 production. Our study reveals bacterial immune-evasion tactics and identifies a potential therapeutic target for treating infectious diseases caused by nontuberculous mycobacteria.