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

• Published in: bioRxiv
• Main Authors: Stephen Adonai Leon Icaza, Bagayoko, Salimata, Verge, Romain, Iakobachvili, Nino, Ferrand, Chloe, Aydogan, Talip, Bernard, Celia, Angelique Sanchez Dafun, Murris-Espin, Marlene, Mazieres, Julien, Bordignon, Pierre Jean, Mazeres, Serge, Pascale Bernes Lasserre, Rame, Victoria, Lagarde, Jean-Michel, Marcoux, Julien, Bousquet, Marie Pierre, Chalut, Christian, Guilhot, Christophe, Clevers, Hans, Peters, Peter J, Molle, Virginie, Lugo-Villarino, Geanncarlo, Kaymeuang Cam, Berry, Laurence, Meunier, Etienne, Cougoule, Celine
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.10.2022
• Subjects: Antioxidants; Apoptosis; Biofilms; Biopsy; Cell death; Chemotherapy; Cystic fibrosis; Infections; Lipid peroxidation; Mycobacterium abscessus; Organoids; Oxidative stress; Patients; Reactive oxygen species; Respiratory tract diseases; Virulence
• DOI: 10.1101/2022.01.03.474765

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. Competing Interest Statement Stephen Adonai Leon-Icaza has nothing to disclose. Salimata Bagayoko has nothing to disclose. Romain Verge has nothing to disclose. Nino Iakobachvili has nothing to disclose. Chloe Ferrand has nothing to disclose. Talip Aydogan has nothing to disclose. Celia Bernard has nothing to disclose. Angelique Sanchez Dafun has nothing to disclose. Marlene Murris-Espin has nothing to disclose. Julien Mazieres reports grants or contracts from Astra Zeneca, Roche and Pierre Fabre; and payment or honoraria for board and expertise (personal and institution) from Merck, Astra Zeneca, BMS, MSD, Roche, Novartis, Daiichi, and Pfizer; outside the submitted work. Pierre Jean Bordignon has nothing to disclose. Serge Mazeres has nothing to disclose. Pascale Bernes-Lasserre has nothing to disclose. Victoria Rame has nothing to disclose. Jean-Michel Lagarde has nothing to disclose. Julien Marcoux has nothing to disclose. Marie Pierre Bousquet has nothing to disclose. Christian Chalut has nothing to disclose. Christophe Guilhot has nothing to disclose. Hans Clevers reports invention on patents related to organoid research. His full disclosure: www.uu.nl/staff/JCClevers/Additional function. Peter J. Peters has nothing to disclose. Virginie Molle has nothing to disclose. Geanncarlo Lugo-Villarino has nothing to disclose. Kaymeuang Cam has nothing to disclose. Laurence Berry has nothing to disclose. Etienne Meunier has nothing to disclose. Celine Cougoule has nothing to disclose. Footnotes * Data were confirmed with organoids from two additional cystic fibrosis patients.