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Pré-Publication, Document De Travail Année : 2022

Druggable redox pathways against M. abscessus in cystic fibrosis patient-derived airway organoids

Salimata Bagayoko
Romain Vergé
Chloé Ferrand
  • Fonction : Auteur
Angelique Sanchez Dafun
Pierre Jean Bordignon
Pascale Bernes-Lasserre
  • Fonction : Auteur
Victoria Ramé
  • Fonction : Auteur
Jean-Michel Lagarde
  • Fonction : Auteur
Marie Pierre Bousquet
  • Fonction : Auteur
Peter Peters
  • Fonction : Auteur
Virginie Molle
Geanncarlo Lugo-Villarino
Kaymeuang Cam
  • Fonction : Auteur
Laurence Berry
  • Fonction : Auteur
Etienne Meunier
Céline Cougoule

Résumé

Abstract 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, 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. 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 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 antioxidants as a potential host-directed strategy to improve Mabs infection control.

Dates et versions

hal-03866382 , version 1 (22-11-2022)

Identifiants

Citer

Stephen Adonai Leon-Icaza, Salimata Bagayoko, Romain Vergé, Nino Iakobachvili, Chloé Ferrand, et al.. Druggable redox pathways against M. abscessus in cystic fibrosis patient-derived airway organoids. 2022. ⟨hal-03866382⟩
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