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

26 Citations (Scopus)

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

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Hydro-Lyases
Mycobacterium
Zebrafish
Growth
Embryonic Structures
Macrophages
Mycolic Acids
Mycobacterium Infections
Granuloma
Abscess
Virulence
Neutrophils
Phenotype
Infection

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. / Halloum, Iman; Carrère-Kremer, Séverine; Blaise, Mickael; Viljoen, Albertus; Bernut, Audrey; Le Moigne, Vincent; Vilchèze, Catherine; Guérardel, Yann; Lutfalla, Georges; Herrmann, Jean Louis; Jacobs, William R.; Kremer, Laurent.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 29, 19.07.2016, p. E4228-E4237.

Research output: Contribution to journalArticle

Halloum, I, Carrère-Kremer, S, Blaise, M, Viljoen, A, Bernut, A, Le Moigne, V, Vilchèze, C, Guérardel, Y, Lutfalla, G, Herrmann, JL, Jacobs, WR & 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, vol. 113, no. 29, pp. E4228-E4237. https://doi.org/10.1073/pnas.1605477113
Halloum, Iman ; Carrère-Kremer, Séverine ; Blaise, Mickael ; Viljoen, Albertus ; Bernut, Audrey ; Le Moigne, Vincent ; Vilchèze, Catherine ; Guérardel, Yann ; Lutfalla, Georges ; Herrmann, Jean Louis ; Jacobs, William R. ; Kremer, Laurent. / Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 29. pp. E4228-E4237.
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AU - Carrère-Kremer, Séverine

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AU - Viljoen, Albertus

AU - Bernut, Audrey

AU - Le Moigne, Vincent

AU - Vilchèze, Catherine

AU - Guérardel, Yann

AU - Lutfalla, Georges

AU - Herrmann, Jean Louis

AU - Jacobs, William R.

AU - Kremer, Laurent

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AB - 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.

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