|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.
|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|
|PubMed:||27385830 Full text @ Proc. Natl. Acad. Sci. USA|
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):E4228-37.
ABSTRACTMycobacterium 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.