M. abscessus (Mabs) infections have heterogeneous clinical outcomes in people with cystic fibrosis (pwCF). The contribution of Mabs dominant circulating clones (DCCs) or morphotypes to the development of pulmonary disease is unclear.

We aim to define the pathogenicity of CF Mabs strains in pulmonary epithelial cells and in mouse models of Mabs respiratory infection.

We collected 11 longitudinal Mabs isolates from five pwCF at the early asymptomatic and Mabs pulmonary disease phases. We performed morphotype (rough vs smooth) and WGS analysis of Mabs, and analysed host transcriptomic response induced by CF isolates in a CF epithelial cell line. We also tested the virulence of Mabs clinical strains in mouse models of acute and chronic lung infection by FACS and Visium spatial transcriptomics.

Epithelial cells infected with DCC1 strains had a higher pro-inflammatory response than DCC2 strains, and morphotype was the main bacterial driver of more than 2,000 host differentially expressed genes. Then, we tested in-vivo the pathogenicity of two longitudinal strains belonging to DCC1 and displaying different morphotypes. Late DCC1 rough strain persisted with a higher bacterial burden and inflammatory response, compared to the earlier DCC1 smooth strain in an acute infection model. Moreover, DCC1 rough strain persisted with a higher inflammatory burden (neutrophils and CD4⁺ T cells) than DCC1 smooth strain during chronic lung infection. Visium spatial transcriptomics confirmed tissue M1 macrophages gene signatures in inflamed/infected tissues.

Our findings suggest that rough Mabs strains from DCC1, persisting in the CF lung may cause severe respiratory infections.