New mouse model reveals strain-driven severity in MAC lung disease

Mycobacterium avium complex (MAC) is the leading cause of non-tuberculous mycobacterial pulmonary disease (NTM-PD), a chronic lung infection that can follow very different paths in different people. That clinical variability has been hard to reproduce in the lab, and existing mouse models have struggled to mimic both the range of pathological changes and the way different strains respond to treatment. In work led by corresponding author Shintaro Seto, researchers set out to test whether diverse clinical MAC strains would produce different disease courses in a commonly used mouse strain. They evaluated five clinical MAC isolates in immunocompetent BALB/c mice, including a newly identified, highly virulent isolate named NBRC112750. By comparing how these strains grew in the lungs and what kinds of lesions they produced, the team hoped to create a model that better reflects the human condition and could be used to study why some infections progress while others remain controlled.

The study tested five clinical MAC strains in BALB/c mice and identified two—FKJ-1 and NBRC112750—that caused progressive pulmonary infection with rising bacterial burdens and extensive lung involvement by 25 weeks post-infection. Both FKJ-1 and NBRC112750 led to the formation of necrotizing granulomas resembling those reported in M. tuberculosis-infected C3HeB/FeJ mice. These necrotic lesions were described as featuring neutrophilic infiltration, foamy macrophages, and collagen encapsulation. Using the FKJ-1 strain, the team also developed an inhalation infection model in which low-dose exposure reproduced the necrotizing granulomas, demonstrating that aerosolized challenge can mimic the pathological features. Importantly, although FKJ-1 showed in vitro drug susceptibility, infections with this strain responded poorly to standard therapy in the mouse model, highlighting strain-dependent variability in treatment efficacy.

These findings matter because they deliver a mouse model that captures both the pathological hallmarks and the therapeutic challenges of MAC-PD as seen in people. A model that produces necrotizing granulomas and shows a mismatch between in vitro drug susceptibility and in vivo treatment response gives researchers a practical platform for studying MAC pathogenesis. It can help clarify why some strains like NBRC112750 and FKJ-1 drive progressive disease and why standard therapy may fail despite laboratory susceptibility tests. The inhalation version of the model also mirrors a likely route of exposure, which is useful for testing interventions that aim to prevent or treat early lung infection. Overall, this work provides a tool to evaluate novel therapies and to explore strain-specific mechanisms that underlie variable clinical outcomes in NTM-PD.