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


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 antimicrobials1,2. 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 acids3,4. 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.

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Figure 1: Absence of ICL does not affect growth or stationary phase survival in vitro.
Figure 2: ICL is required for persistence and virulence of M. tuberculosis in immune-competent mice.
Figure 3: The level of ICL–GFP is higher in bacteria within activated macrophages.
Figure 4: The requirement for ICL is determined by the immune status of the host cell.
Figure 5: The Δicl mutant is lethal to immune-deficient mice.


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J.D.M. and colleagues generated the data shown in Figs 1, 2, and 5. K.H.z.B. and colleagues generated the data shown in Figs 3 and 4. We thank B. R. Bloom for helpful discussions. J.D.M. was supported by a fellowship from the Helen Hay Whitney Foundation. J.D.M., E.J.M., W.T.C., K.H.z.B., A.M., D.S. and D.G.R. were supported by a grant from Glaxo Wellcome. All authors were supported by funds from the US Public Health Service.

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Correspondence to David G. Russell.

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McKinney, J., zu Bentrup, K., Muñoz-Elías, E. et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735–738 (2000).

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