Title :

Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent

Author(s) :

Halloum, Iman [Auteur]
Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé [CPBS]
Carrère-Kremer, Séverine [Auteur]
Pathogénèse et contrôle des infections chroniques (PCCI)
Blaise, Mickaël [Auteur]
Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé [CPBS]
Viljoen, Albertus [Auteur]
Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé [CPBS]
Bernut, Audrey [Auteur]
Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé [CPBS]
Le Moigne, Vincent [Auteur]
Infection et inflammation [2I]
Vilchèze, Catherine [Auteur]
Albert Einstein College of Medicine [New York]
Guerardel, Yann [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Lutfalla, Georges [Auteur]
Dynamique des interactions membranaires normales et pathologiques [DIMNP]
Herrmann, Jean-Louis [Auteur]
Infection et inflammation [2I]
Jacobs, William R. [Auteur]
Albert Einstein College of Medicine [New York]
Kremer, Laurent [Auteur]
Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé [CPBS]

Journal title :

Proceedings of the National Academy of Sciences of the United States of America

Abbreviated title :

Proc. Natl. Acad. Sci. U.S.A.

Volume number :

113

Pages :

E4228-4237

Publication date :

2016-07-19

ISSN :

1091-6490

English keyword(s) :

Zebrafish
cording
M. abscessus
Virulence
dehydratase

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

Mycobacterium abscessus (Mabs) is a rapidly growing Mycobacterium and an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with ...
Show more >Mycobacterium abscessus (Mabs) is a rapidly growing Mycobacterium and an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with increased virulence in zebrafish, which involves the formation of massive serpentine cords, abscesses, and rapid larval death. Generating a cord-deficient Mabs mutant would allow us to address the contribution of cording in the physiopathological signs of the R variant. Herein, a deletion mutant of MAB_4780, encoding a dehydratase, distinct from the β-hydroxyacyl-ACP dehydratase HadABC complex, was constructed in the R morphotype. This mutant exhibited an alteration of the mycolic acid composition and a pronounced defect in cording. This correlated with an extremely attenuated phenotype not only in wild-type but also in immunocompromised zebrafish embryos lacking either macrophages or neutrophils. The abolition of granuloma formation in embryos infected with the dehydratase mutant was associated with a failure to replicate in macrophages, presumably due to limited inhibition of the phagolysosomal fusion. Overall, these results indicate that MAB_4780 is required for Mabs to successfully establish acute and lethal infections. Therefore, targeting MAB_4780 may represent an attractive antivirulence strategy to control Mabs infections, refractory to most standard chemotherapeutic interventions. The combination of a dehydratase assay with a high-resolution crystal structure of MAB_4780 opens the way to identify such specific inhibitors.Show less >

Language :

Anglais

Audience :

Non spécifiée

ANR Project :

Identification et Visualisation des Mécanismes Permettant l'Acquisition d'un Phénotype Invasif chez les Mycobactéries Pathogènes à Croissance Rapide

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Chemical Glycobiology

Submission date :

2020-02-12T15:11:11Z
2021-05-07T07:23:34Z