Expanding the scope of Mycobacterium abscessus reference strains to improve pulmonary disease modeling.

Mycobacterium abscessus (Mab) pulmonary disease is an emerging clinical challenge, particularly in individuals with immunosuppression or structural lung disease. No US Food and Drug Administration (FDA)-approved therapies exist, and current multidrug regimens are prolonged, toxic and achieve low cure rates, highlighting the need for improved treatments. Progress depends on preclinical models that faithfully recapitulate human disease, for which strain selection is critical. The widely used reference strain, ATCC 19977, was isolated from a non-pulmonary source but became the default owing to early availability. To assess its relevance for modeling pulmonary disease, we compared it with 15 clinical Mab isolates from lung infections across the United States. In vitro and in a validated mouse lung infection model, ATCC 19977 differed markedly from clinical isolates, exhibiting rapid systemic dissemination, limited lung granuloma formation and early mortality. In contrast, clinical isolates demonstrated greater pulmonary tropism, reduced dissemination and robust lung pathology. We propose a panel of pulmonary clinical isolates representing major Mab subspecies and phenotypes for lung research. These isolates more accurately recapitulate human disease and are expected to enhance the translational relevance of mechanistic and therapeutic studies.