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

Novel treatment strategies are urgently needed to combat Mycobacterium avium complex (MAC) pulmonary disease (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 modelled 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 that 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 stabilisation 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.