Strain-dependent disease progression and necrotizing granuloma formation in a murine model induced by virulent strains of <i>Mycobacterium avium</i> complex

Mycobacterium avium complex (MAC) is the leading cause of non-tuberculous mycobacterial pulmonary disease (NTM-PD), a chronic infection with a heterogeneous clinical course. Although murine models of MAC-PD exist, faithfully reproducing the progressive pathology and variable treatment responses of the disease remains challenging. Here, we assessed the virulence of five clinical MAC strains in immunocompetent BALB/c mice, including a newly identified highly virulent isolate, NBRC112750. Two strains, FKJ-1 and NBRC112750, induced progressive pulmonary infection characterized by rising bacterial loads and extensive lung involvement over 25 weeks postinfection. In BALB/c mice, both strains produced necrotizing granulomas resembling those observed in M. tuberculosis -infected C3HeB/FeJ mice, characterized by neutrophilic infiltration, foamy macrophages, and collagen encapsulation. We further established an inhalation-based infection model using FKJ-1, in which low-dose exposure reproducibly generated necrotizing granulomas. Despite demonstrating in vitro drug susceptibility, FKJ-1 responded poorly to standard antimicrobial, therapy indicating strain-dependent variability in treatment efficacy. Together, these findings establish a murine model that accurately reflects the critical pathological and therapeutic features of MAC-PD and provides a valuable platform for studying MAC pathogenesis and evaluating novel therapies. Importance The global incidence of pulmonary disease (PD) caused by non-tuberculous mycobacteria, particularly Mycobacterium avium complex (MAC), is increasing. However, the mechanisms underlying its pathological heterogeneity and variable treatment outcomes remain poorly understood. Here, we establish a murine model that recapitulates the key features of progressive MAC-PD, including necrotizing granuloma formation. We also demonstrate strain-specific differences in treatment responses despite comparable in vitro drug susceptibility. Notably, highly virulent strains induced necrotizing granulomatous lesions similar to those observed in patients with tuberculosis or MAC-PD. This study provides a valuable in vivo platform for investigating host-pathogen interactions, elucidating strain-dependent pathogenesis, and optimizing treatment strategies for MAC-PD.