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Unravelling the pathogenicity of Mycobacterium abscessus clinical isolates in CF pulmonary epithelial cell and mouse models of respiratory infection

F Di Marco(1) F Saliu(1) A Spitaleri(1) F Nicola(1) M Rossi(1) L Cariani(2) D M Cirillo(1) N I Lorè(1)

1:San Raffaele Scientific Institute; 2:Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

Mycobacterium abscessus (MA) infections in Cystic fibrosis (CF) patients display heterogeneous clinical outcomes. To date, the contribution to MA pulmonary disease (MA-PD) development by dominant circulating clones (DCCs) or morphotypes, remains to be elucidated. We aim at defining pathogenicity of CF MA clinical strains in CF pulmonary epithelial cell and mouse models of MA respiratory infection.

We collected eleven longitudinal MA strains isolated from five patients both at the early asymptomatic and MA-PD phase. We performed morphotype (rough and smooth phenotype) and whole genome sequencing (WGS) analysis. Moreover, we studied the host response induced by CF isolates in CF epithelial cells (CFF-16HBEgeCFTRΔF508) by host RNA sequencing and cytokines release. We also tested the virulence of MA clinicals strains in mouse models of lung infection.

Epithelial cells infected with DCC1 strains displays a higher proinflammatory response than DCC2 strains. Moreover, we found out that morphotype (smooth vs rough strains) is the main bacterial feature driving over 3000 host differentially expressed genes. This was confirmed also by the evaluation of IL6 and IL8 protein levels upon infection. Then, we tested the in vivo pathogenicity of two longitudinal strains from the same patient, belonging to DCC1 and displaying a different morphotype. Longitudinal persisted rough strain displayed a higher bacterial burden and proinflammatory response, such as airway monocyte recruitment, than smooth strain in mouse models of acute and chronic lung infection.

Our findings suggest that rough DCC1 strains persisted within CF lung may cause more severe respiratory infections.


Supported by Italian CF foundation FFC#23_2020

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