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ZFIN ID: ZDB-PUB-160708-1
Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent
Halloum, I., Carrère-Kremer, S., Blaise, M., Viljoen, A., Bernut, A., Le Moigne, V., Vilchèze, C., Guérardel, Y., Lutfalla, G., Herrmann, J.L., Jacobs, W.R., Kremer, L.
Date: 2016
Source: Proceedings of the National Academy of Sciences of the United States of America   113(29): E4228-37 (Journal)
Registered Authors: Lutfalla, Georges
Keywords: M. abscessus, cording, dehydratase, virulence, zebrafish
MeSH Terms:
  • Animals
  • Cell Line
  • Embryo, Nonmammalian/enzymology
  • Embryo, Nonmammalian/immunology
  • Embryo, Nonmammalian/microbiology
  • Hydro-Lyases/physiology*
  • Macrophages/immunology
  • Macrophages/microbiology
  • Mice
  • Mycobacterium/pathogenicity*
  • Mycobacterium Infections/enzymology*
  • Mycobacterium Infections/microbiology
  • Neutrophils/immunology
  • Virulence
  • Zebrafish/immunology
  • Zebrafish/metabolism
  • Zebrafish/microbiology
  • Zebrafish Proteins/physiology*
PubMed: 27385830 Full text @ Proc. Natl. Acad. Sci. USA
FIGURES
ABSTRACT
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.
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