Stephen Adonai Leon-Icaza, Salimata Bagayoko, Romain Vergé, Nino Iakobachvili, Chloé Ferrand, Talip Aydogan, Célia Bernard, Angelique Sanchez Dafun, Marlène Murris-Espin, Julien Mazières, Pierre Jean Bordignon, Serge Mazères, Pascale Bernes-Lasserre, Victoria Ramé, Jean-Michel Lagarde, Julien Marcoux, Marie-Pierre Bousquet, Christian Chalut, Christophe Guilhot, Hans Clevers, Peter J Peters, Virginie Molle, Geanncarlo Lugo-Villarino, Kaymeuang Cam, Laurence Berry, Etienne Meunier, Céline Cougoule
{"title":"Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids.","authors":"Stephen Adonai Leon-Icaza, Salimata Bagayoko, Romain Vergé, Nino Iakobachvili, Chloé Ferrand, Talip Aydogan, Célia Bernard, Angelique Sanchez Dafun, Marlène Murris-Espin, Julien Mazières, Pierre Jean Bordignon, Serge Mazères, Pascale Bernes-Lasserre, Victoria Ramé, Jean-Michel Lagarde, Julien Marcoux, Marie-Pierre Bousquet, Christian Chalut, Christophe Guilhot, Hans Clevers, Peter J Peters, Virginie Molle, Geanncarlo Lugo-Villarino, Kaymeuang Cam, Laurence Berry, Etienne Meunier, Céline Cougoule","doi":"10.1371/journal.ppat.1011559","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10449475/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Pathogens","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1371/journal.ppat.1011559","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/8/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"Immunology and Microbiology","Score":null,"Total":0}
引用次数: 0
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, 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.
期刊介绍:
Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.