The organoid revolution to assess mycobacterial pulmonary infections
S A Leon-Icaza(1) S Bagayoko(1) R Vergé(1) N Iakobachvili(2) C Ferrand(1) T Aydogan(3) C Bernard(1) A Sanchez Dafun(7) M Murris-Espin(4) J Mazières(4) P J Bordignon(1) S Mazères(7) P Bernes-Lasserre(5) V Ramé(5) J M Lagarde(5) J Marcoux(7) M P Bousquet(7) C Chalut(7) C Guilhot(7) H Clevers(6) P J Peters(2) V Molle(3) G Lugo-Villarino(7) K Cam(7) L Berry(3) E Meunier(1) C Cougoule(1)
1:Immune Detection and Elimination of Pathogens, Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France; 2:M4i Nanoscopy Division, Maastricht University, Maastricht, Netherlands; 3:Laboratory of Pathogen Host Interactions (LPHI), Université Montpellier, CNRS, Montpellier, France; 4:Service de Pneumologie, Hôpital Larrey, CHU de Toulouse, Toulouse, France; 5:Imactiv-3D SAS, 1 Place Pierre POTIER, 31100 Toulouse, France; 6:Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Netherlands; 7:Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
Mycobacterium abscessus (Mabs) is an opportunistic pathogen whose incidence and prevalence have risen in recent years owing to the increasing of immunocompromised and vulnerable individuals, such as cystic fibrosis (CF) patients. Nevertheless, the models for determining the host and bacterial factors that lead to Mabs pathology in CF patients are still rudimentary. In our project, we applied the human airway organoid (AO) technology to decipher early events during colonization and infection of the lung epithelium by Mabs, as well as the efficacy of potential new treatments.
First, we show that airway organoids derived from CF patients (CF-AO) present a thicker epithelium, accumulate mucus, and undergo increased oxidative stress, lipid peroxidation, and cell death, key features of CF disease. Next, we reveal that in Mabs infected-AOs the smooth morphotype (S) forms aggregates, while the rough (R) form cord serpentines. Along Mabs infection, the redox pathways were the most dysregulated in the organoids.
Finally, we demonstrate that Mabs take advantage of the exacerbated oxidative environment in the CF-AOs to thrive. By boosting detoxification pathways with NRF2 agonists (master regulator of the antioxidant pathways), such as sulforaphane, the basal levels of reactive oxygen species (ROS) and cell death in CF-AOs decreased via the enrichment of the NQO1 mRNA pool, those contributing to better control of Mabs growth. This opens new possible druggable pathways to better control Mabs infection.