Immunopathological outcomes are isolate-dependent in chronic Mycobacterium avium complex pulmonary disease

Novel treatment strategies are urgently needed to combat Mycobacterium avium complex pulmonary disease (MAC-PD). Animal models are important for screening therapeutic strategies, but their ability to reproduce human-like immunopathology, and impaired respiratory function is poorly characterised. We modeled chronic lung infection in BALB/c mice over 20 weeks with three isolates of MAC (MAC101, MAC104 and MAC2285R) to compare bacterial growth, histological injury, immune cellular dynamics and respiratory function. We found MAC101 caused a proliferative infection over 20 weeks, associated with a strong adaptive response, progressive granulomatous inflammation and increasing respiratory effort. For MAC104, lung bacterial burden rose initially but fell after week 12, accompanied by increased regulatory T-cell response and stabilization of pathological and respiratory changes. By contrast, MAC2285R caused a low-virulence, non-proliferative infection associated with a strong myeloid cell response, modest histopathological change and increased respiratory effort. Immune cell dynamics in chronic murine MAC-PD correlate with bacterial burden and pathology, and are strongly MAC-isolate dependent. These findings provide a spectrum of quantifiable and clinically-relevant disease outcomes to facilitate the preclinical screening of novel antimicrobial and host-directed therapies for MAC-PD.