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

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

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

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 CleversPeter J Peters, Virginie Molle, Geanncarlo Lugo-Villarino, Kaymeuang Cam, Laurence Berry, Etienne Meunier, Céline Cougoule

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

3 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	e1011559
Tijdschrift	PLoS Pathogens
Volume	19
Nummer van het tijdschrift	8
DOI's	https://doi.org/10.1371/journal.ppat.1011559
Status	Gepubliceerd - aug. 2023

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Leon-Icaza, S. A., Bagayoko, S., Vergé, R., Iakobachvili, N., Ferrand, C., Aydogan, T., Bernard, C., Sanchez Dafun, A., Murris-Espin, M., Mazières, J., Bordignon, P. J., Mazères, S., Bernes-Lasserre, P., Ramé, V., Lagarde, J.-M., Marcoux, J., Bousquet, M.-P., Chalut, C., Guilhot, C., ... Cougoule, C. (2023). Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids. PLoS Pathogens, 19(8), e1011559. https://doi.org/10.1371/journal.ppat.1011559

@article{5ce34b617a16444ba06ce9c8017a4c4f,

title = "Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids",

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.",

keywords = "Humans, Cystic Fibrosis/drug therapy, Mycobacterium abscessus, Antioxidants, Oxidation-Reduction, Oxidative Stress",

author = "Leon-Icaza, {Stephen Adonai} and Salimata Bagayoko and Romain Verg{\'e} and Nino Iakobachvili and Chlo{\'e} Ferrand and Talip Aydogan and C{\'e}lia Bernard and {Sanchez Dafun}, Angelique and Marl{\`e}ne Murris-Espin and Julien Mazi{\`e}res and Bordignon, {Pierre Jean} and Serge Maz{\`e}res and Pascale Bernes-Lasserre and Victoria Ram{\'e} and Jean-Michel Lagarde and Julien Marcoux and Marie-Pierre Bousquet and Christian Chalut and Christophe Guilhot and Hans Clevers and Peters, {Peter J} and Virginie Molle and Geanncarlo Lugo-Villarino and Kaymeuang Cam and Laurence Berry and Etienne Meunier and C{\'e}line Cougoule",

note = "Copyright: {\textcopyright} 2023 Leon-Icaza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2023",

month = aug,

doi = "10.1371/journal.ppat.1011559",

language = "English",

volume = "19",

pages = "e1011559",

journal = "PLoS Pathogens",

issn = "1553-7366",

publisher = "Public Library of Science",

number = "8",

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Leon-Icaza, SA, Bagayoko, S, Vergé, R, Iakobachvili, N, Ferrand, C, Aydogan, T, Bernard, C, Sanchez Dafun, A, Murris-Espin, M, Mazières, J, Bordignon, PJ, Mazères, S, Bernes-Lasserre, P, Ramé, V, Lagarde, J-M, Marcoux, J, Bousquet, M-P, Chalut, C, Guilhot, C, Clevers, H, Peters, PJ, Molle, V, Lugo-Villarino, G, Cam, K, Berry, L, Meunier, E & Cougoule, C 2023, 'Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids', PLoS Pathogens, vol. 19, nr. 8, blz. e1011559. https://doi.org/10.1371/journal.ppat.1011559

TY - JOUR

T1 - Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids

AU - Leon-Icaza, Stephen Adonai

AU - Bagayoko, Salimata

AU - Vergé, Romain

AU - Iakobachvili, Nino

AU - Ferrand, Chloé

AU - Aydogan, Talip

AU - Bernard, Célia

AU - Sanchez Dafun, Angelique

AU - Murris-Espin, Marlène

AU - Mazières, Julien

AU - Bordignon, Pierre Jean

AU - Mazères, Serge

AU - Bernes-Lasserre, Pascale

AU - Ramé, Victoria

AU - Lagarde, Jean-Michel

AU - Marcoux, Julien

AU - Bousquet, Marie-Pierre

AU - Chalut, Christian

AU - Guilhot, Christophe

AU - Clevers, Hans

AU - Peters, Peter J

AU - Molle, Virginie

AU - Lugo-Villarino, Geanncarlo

AU - Cam, Kaymeuang

AU - Berry, Laurence

AU - Meunier, Etienne

AU - Cougoule, Céline

N1 - Copyright: © 2023 Leon-Icaza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - Humans

KW - Cystic Fibrosis/drug therapy

KW - Mycobacterium abscessus

KW - Antioxidants

KW - Oxidation-Reduction

KW - Oxidative Stress

U2 - 10.1371/journal.ppat.1011559

DO - 10.1371/journal.ppat.1011559

M3 - Article

C2 - 37619220

SN - 1553-7366

VL - 19

SP - e1011559

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 8

ER -

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

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