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

Iman Halloum, Séverine Carrère-Kremer, Mickael Blaise, Albertus Viljoen, Audrey Bernut, Vincent Le Moigne, Catherine Vilchèze, Yann Guérardel, Georges Lutfalla, Jean Louis Herrmann, William R. Jacobs, Laurent Kremer

Research output: Contribution to journalArticle

28 Scopus citations

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 highresolution crystal structure of MAB-4780 opens the way to identify such specific inhibitors.

Original languageEnglish (US)
Pages (from-to)E4228-E4237
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number29
DOIs
StatePublished - Jul 19 2016

Keywords

  • Cording
  • Dehydratase
  • M. abscessus
  • Virulence
  • Zebrafish

ASJC Scopus subject areas

  • General

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    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. (2016). Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. Proceedings of the National Academy of Sciences of the United States of America, 113(29), E4228-E4237. https://doi.org/10.1073/pnas.1605477113