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-Elías, Andras Miczak, Bing Chen, Wai-Tsing Chan, Dana Swenson, James C. Sacchettini, William R. Jacobs and David G. Russell ()
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John D. McKinney: Howard Hughes Medical Institute, Albert Einstein College of Medicine
Kerstin Höner zu Bentrup: Department of Molecular Microbiology Washington University School of Medicine
Ernesto J. Muñoz-Elías: The Rockefeller University
Andras Miczak: Department of Molecular Microbiology Washington University School of Medicine
Bing Chen: Howard Hughes Medical Institute, Albert Einstein College of Medicine
Wai-Tsing Chan: The Rockefeller University
Dana Swenson: Department of Molecular Microbiology Washington University School of Medicine
James C. Sacchettini: Department of Biochemistry and Biophysics Texas A&M University
William R. Jacobs: Howard Hughes Medical Institute, Albert Einstein College of Medicine
David G. Russell: Department of Molecular Microbiology Washington University School of Medicine

Nature, 2000, vol. 406, issue 6797, 735-738

Abstract: 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 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.

Date: 2000
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DOI: 10.1038/35021074

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