1. Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA
2. Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue , St. Louis, Missouri 63110, USA
3. The Rockefeller University, 1230 York Avenue, New York, New York 10021 , USA
4. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA
5. Present addresses: The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA (J.D.M. and W.-T.C.); Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 , USA (K.H.z.B., D.S. and D.G.R.); Department of Microbiology, Albert Szent-Gyorgi Medical University, Szeged POB 8-6701 , Hungary (A.M.).

Correspondence to: David G. Russell^2,3 Correspondence and requests for materials should be addressed to D.G.R. (e-mail: Email: dgr8@cornell.edu).

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^{1, 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 acids^{3, 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 icl bacteria in interferon- knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the icl 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.

1. Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA
2. Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue , St. Louis, Missouri 63110, USA
3. The Rockefeller University, 1230 York Avenue, New York, New York 10021 , USA
4. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA
5. Present addresses: The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA (J.D.M. and W.-T.C.); Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 , USA (K.H.z.B., D.S. and D.G.R.); Department of Microbiology, Albert Szent-Gyorgi Medical University, Szeged POB 8-6701 , Hungary (A.M.).

Correspondence to: David G. Russell^2,3 Correspondence and requests for materials should be addressed to D.G.R. (e-mail: Email: dgr8@cornell.edu).