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

## TL;DR

Different strains of Mycobacterium avium complex cause varying levels of lung disease severity and immune responses in mice.

## Contribution

The study reveals isolate-specific immunopathological outcomes in chronic Mycobacterium avium complex pulmonary disease.

## Key findings

- MAC101 caused progressive granulomatous inflammation and strong adaptive immune response.
- MAC104 showed reduced bacterial burden after week 12 with increased regulatory T-cells.
- MAC2285R caused low-virulence infection with minimal pathology and strong myeloid cell response.

## Abstract

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.

Summary: Clinically relevant outcomes in chronic Mycobacterium avium complex pulmonary disease (including bacterial burden, histological injury, immune cellular dynamics and respiratory function) are variably dependent on the bacterial isolate.