Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase

John D. McKinney, Kerstin Höner Zu Bentrup, Ernesto J. Muñoz-Elias, A. Miczák, Bing Chen, Wal Tsing Chan, Dana Swenson, James C. Sacchettini, William R. Jacobs, David G. Russell

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Abstract

Mycobacterium tuberculosis claims more human lives each year than any other bacterial pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Here we report that persistence of M. tuberculosis in mice is facilitated by isocitrate lyase (ICL), an enzyme essential for the metabolism of fatty acids. Disruption of the icl gene attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection. A link between the requirement for ICL and the immune status of the host was established by the restored virulence of Δicl bacteria in interferon-γ knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the Δicl mutant was markedly attenuated for survival in activated but not resting macrophages. These data suggest that the metabolism of M. tuberculosis in vivo is profoundly influenced by the host response to infection, an observation with important implications for the treatment of chronic tuberculosis.

Original languageEnglish
Pages (from-to)735-738
Number of pages4
JournalNature
Volume406
Issue number6797
DOIs
Publication statusPublished - Aug 17 2000

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Isocitrate Lyase
Mycobacterium tuberculosis
Macrophages
Enzymes
Infection
Virulence
Bacteria
Bacterial Genes
Essential Fatty Acids
Macrophage Activation
Adaptive Immunity
Knockout Mice
Interferons
Tuberculosis
Observation
Survival
glyoxylic acid
Growth

ASJC Scopus subject areas

  • General

Cite this

McKinney, J. D., Höner Zu Bentrup, K., Muñoz-Elias, E. J., Miczák, A., Chen, B., Chan, W. T., ... Russell, D. G. (2000). Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature, 406(6797), 735-738. https://doi.org/10.1038/35021074

Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. / McKinney, John D.; Höner Zu Bentrup, Kerstin; Muñoz-Elias, Ernesto J.; Miczák, A.; Chen, Bing; Chan, Wal Tsing; Swenson, Dana; Sacchettini, James C.; Jacobs, William R.; Russell, David G.

In: Nature, Vol. 406, No. 6797, 17.08.2000, p. 735-738.

Research output: Contribution to journalArticle

McKinney, JD, Höner Zu Bentrup, K, Muñoz-Elias, EJ, Miczák, A, Chen, B, Chan, WT, Swenson, D, Sacchettini, JC, Jacobs, WR & Russell, DG 2000, 'Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase', Nature, vol. 406, no. 6797, pp. 735-738. https://doi.org/10.1038/35021074
McKinney, John D. ; Höner Zu Bentrup, Kerstin ; Muñoz-Elias, Ernesto J. ; Miczák, A. ; Chen, Bing ; Chan, Wal Tsing ; Swenson, Dana ; Sacchettini, James C. ; Jacobs, William R. ; Russell, David G. / Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. In: Nature. 2000 ; Vol. 406, No. 6797. pp. 735-738.
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