In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 8 ( 2023-8-24), p. e1011559-
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011559
DOI:
10.1371/journal.ppat.1011559.g001
DOI:
10.1371/journal.ppat.1011559.g002
DOI:
10.1371/journal.ppat.1011559.g003
DOI:
10.1371/journal.ppat.1011559.g004
DOI:
10.1371/journal.ppat.1011559.g005
DOI:
10.1371/journal.ppat.1011559.s001
DOI:
10.1371/journal.ppat.1011559.s002
DOI:
10.1371/journal.ppat.1011559.s003
DOI:
10.1371/journal.ppat.1011559.s004
DOI:
10.1371/journal.ppat.1011559.s005
DOI:
10.1371/journal.ppat.1011559.s006
DOI:
10.1371/journal.ppat.1011559.s007
DOI:
10.1371/journal.ppat.1011559.s008
DOI:
10.1371/journal.ppat.1011559.s009
DOI:
10.1371/journal.ppat.1011559.s010
DOI:
10.1371/journal.ppat.1011559.s011
DOI:
10.1371/journal.ppat.1011559.s012
DOI:
10.1371/journal.ppat.1011559.s013
DOI:
10.1371/journal.ppat.1011559.r001
DOI:
10.1371/journal.ppat.1011559.r002
DOI:
10.1371/journal.ppat.1011559.r003
DOI:
10.1371/journal.ppat.1011559.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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