부산대학교 도서관

Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. To date, our knowledge on the host and bacterial determinants driving Mabs pathology in CF patient lung remains rudimentary. Here, we used human airway organoids (AOs) microinjected with smooth (S) or rough (R-)Mabs to evaluate bacteria fitness, host responses to infection, and new treatment efficacy. We show that S Mabs formed biofilm, and R Mabs formed cord serpentines and displayed a higher virulence. While Mabs infection triggers enhanced oxidative stress, pharmacological activation of antioxidant pathways resulted in better control of Mabs growth and reduced virulence. Genetic and pharmacological inhibition of the CFTR is associated with better growth and higher virulence of S and R Mabs. Finally, pharmacological activation of antioxidant pathways inhibited Mabs growth, at least in part through the quinone oxidoreductase NQO1, and improved efficacy in combination with cefoxitin, a first line antibiotic. In conclusion, we have established AOs as a suitable human system to decipher mechanisms of CF-driven respiratory infection by Mabs and propose boosting of the NRF2-NQO1 axis as a potential host-directed strategy to improve Mabs infection control. Author summary: Pulmonary infection by Non Tuberculosis Mycobacteria is a rising concern for patients with cystic fibrosis (CF), especially Mycobacterium abscessus (Mabs). Mabs exists as two morphotypes. CF patients are generally infected by the S morphotype present in the environment, which can switch to the R morphotype displaying higher virulence. Due to its resistance to antibiotics, treatments againt Mabs often fail, calling for complementary therapeutical strategies. Here we adapted the human airway organoid technology to model Mabs infection in the context of CF, decipher mechanisms of host-pathogen interaction that can be pharmacologically targeted to improve infection control. We found that Mabs R induces higher host oxidative stress and cell death, hallmarks of its virulence, which are enhanced in the CF context. Boosting the host oxidative pathway using antioxidants improves infection control by a frontline antibiotic. Our study provides CF patient-derived airway organoids as a relevant human-based, animal-free system for CF-driven Mabs infection and evaluation of innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]