{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:13:35Z","timestamp":1790702015576,"version":"4.1.0"},"reference-count":100,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:00:00Z","timestamp":1692835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006342","name":"Association Vaincre la Mucoviscidose","doi-asserted-by":"publisher","award":["N\u00b0RF20210502852\/1\/1\/48"],"award-info":[{"award-number":["N\u00b0RF20210502852\/1\/1\/48"]}],"id":[{"id":"10.13039\/501100006342","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gr\u00e9gory Lemarchal","award":["N\u00b0RF20210502852\/1\/1\/48"],"award-info":[{"award-number":["N\u00b0RF20210502852\/1\/1\/48"]}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","award":["AJE20151034460"],"award-info":[{"award-number":["AJE20151034460"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CNRS ATIP avenir and ERC StG","award":["INFLAME 804249"],"award-info":[{"award-number":["INFLAME 804249"]}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","award":["FDT202106012794"],"award-info":[{"award-number":["FDT202106012794"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CNRS","award":["IEA 300134"],"award-info":[{"award-number":["IEA 300134"]}]},{"name":"Campus France PHC Van Gogh","award":["40577ZE"],"award-info":[{"award-number":["40577ZE"]}]},{"name":"ZonMW 3R\u2019s","award":["114021005"],"award-info":[{"award-number":["114021005"]}]},{"name":"LINK program from the Province of Limburg, the Netherlands"},{"name":"Nuffic Van Gogh Programme","award":["VGP.17\/10"],"award-info":[{"award-number":["VGP.17\/10"]}]},{"name":"ANR JCJC ProteasoRegMS"},{"name":"La R\u00e9gion Languedoc-Roussillon","award":["N\u00b0 DRTE\/RSS - ESR_R&S_DF-000061-2018-003268"],"award-info":[{"award-number":["N\u00b0 DRTE\/RSS - ESR_R&S_DF-000061-2018-003268"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Mycobacterium abscessus<\/jats:italic> (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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011559","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T17:23:56Z","timestamp":1692897836000},"page":"e1011559","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids"],"prefix":"10.1371","volume":"19","author":[{"given":"Stephen Adonai","family":"Leon-Icaza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salimata","family":"Bagayoko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Verg\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nino","family":"Iakobachvili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Ferrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talip","family":"Aydogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9lia","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"Sanchez 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Lopes-Pacheco","year":"2019","journal-title":"Front Pharmacol"},{"key":"ppat.1011559.ref003","first-page":"7","article-title":"Mycobacterium abscessus: Environmental bacterium turned clinical nightmare","author":"RC Lopeman","year":"2019","journal-title":"Microorganisms"},{"key":"ppat.1011559.ref004","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.5588\/ijtld.14.0134","article-title":"Advances in the management of pulmonary disease due to Mycobacterium abscessus complex","author":"WJ Koh","year":"2014","journal-title":"International Journal of Tuberculosis and Lung Disease. International Union against Tubercul. and Lung Dis."},{"issue":"Suppl 1","key":"ppat.1011559.ref005","doi-asserted-by":"crossref","first-page":"i1","DOI":"10.1136\/thoraxjnl-2015-207360","article-title":"US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis","volume":"71","author":"RA Floto","year":"2016","journal-title":"Thorax"},{"key":"ppat.1011559.ref006","first-page":"392","article-title":"Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus","volume":"18","author":"MD Johansen","year":"2020","journal-title":"Nature Reviews Microbiology 2020 18:7."},{"key":"ppat.1011559.ref007","first-page":"62","article-title":"Mycobacterium abscessus smooth and rough morphotypes form antimicrobial-tolerant biofilm phenotypes but are killed by acetic acid","author":"G Clary","year":"2018","journal-title":"Antimicrob Agents 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Geol"},{"key":"ppat.1011559.ref034","doi-asserted-by":"crossref","first-page":"e1011318","DOI":"10.1371\/journal.ppat.1011318","article-title":"The cell envelope of Mycobacterium abscessus and its role in pathogenesis","volume":"19","author":"S Parmar","year":"2023","journal-title":"PLoS Pathog"},{"key":"ppat.1011559.ref035","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1128\/JB.01485-09","article-title":"Microscopic Cords, a Virulence-Related Characteristic of Mycobacterium tuberculosis, Are Also Present in Nonpathogenic Mycobacteria","volume":"192","author":"E Juli\u00e1n","year":"2010","journal-title":"J Bacteriol"},{"key":"ppat.1011559.ref036","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1111\/j.1651-2227.1994.tb13229.x","article-title":"Oxygen free radicals and antioxidants in cystic fibrosis: the concept of an oxidant-antioxidant imbalance","volume":"83","author":"BM Winklhofer-Roob","year":"1994","journal-title":"Acta Paediatr 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Soc"},{"key":"ppat.1011559.ref047","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1164\/rccm.202004-1200LE","article-title":"Comparison of Organoid Swelling and In Vivo Biomarkers of CFTR Function to Determine Effects of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation","volume":"202","author":"SY Graeber","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"ppat.1011559.ref048","doi-asserted-by":"crossref","first-page":"L119","DOI":"10.1152\/ajplung.00639.2020","article-title":"CFTR function and clinical response to modulators parallel nasal epithelial organoid swelling","volume":"321","author":"JD Anderson","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ppat.1011559.ref049","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.jcf.2022.01.008","article-title":"Forskolin induced swelling (FIS) assay in intestinal organoids to guide eligibility for compassionate use treatment in a CF patient with a rare genotype","volume":"21","author":"BL Aalbers","year":"2022","journal-title":"J Cyst Fibros"},{"key":"ppat.1011559.ref050","first-page":"52","article-title":"Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function","author":"KM de Winter-De Groot","year":"2018","journal-title":"Eur Respir J"},{"key":"ppat.1011559.ref051","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10863-018-9748-x","article-title":"Aberrant GSH reductase and NOX activities concur with defective CFTR to pro-oxidative imbalance in cystic fibrosis airways","volume":"50","author":"L de Bari","year":"2018","journal-title":"J Bioenerg Biomembr"},{"key":"ppat.1011559.ref052","doi-asserted-by":"crossref","first-page":"e105912","DOI":"10.15252\/embj.2020105912","article-title":"An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells","volume":"40","author":"MM Lamers","year":"2021","journal-title":"EMBO J"},{"key":"ppat.1011559.ref053","doi-asserted-by":"crossref","first-page":"6822","DOI":"10.1073\/pnas.1806308115","article-title":"Differentiated human airway organoids to assess infectivity of emerging influenza virus","volume":"115","author":"J Zhou","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1011559.ref054","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1055\/s-0038-1651495","article-title":"Nontuberculous Mycobacteria in Cystic Fibrosis","volume":"39","author":"BS Furukawa","year":"2018","journal-title":"Semin Respir Crit Care Med"},{"key":"ppat.1011559.ref055","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jcf.2015.09.007","article-title":"Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis","volume":"15","author":"T Qvist","year":"2016","journal-title":"J Cyst 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