Persistence of Mycobacterium tuberculosis in macrophages and mice requiresthe 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 antimicrobials(1,2). Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial met abolism throughout the course of infection remains rudimentary. Here we rep ort that persistence of M. tuberculosis in mice is facilitated by isocitrat e lyase (ICL), an enzyme essential for the metabolism of fatty acids(3,4). Disruption of the icl gene attenuated bacterial persistence and virulence i n 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 Delta icl b acteria in interferon-gamma knockout mice. This link was apparent at the le vel of the infected macrophage: Activation of infected macrophages increase d expression of ICL, and the Delta icl mutant was markedly attenuated for s urvival in activated but not resting macrophages. These data suggest that t he metabolism of M. tuberculosis in vivo is profoundly influenced by the ho st response to infection, an observation with important implications for th e treatment of chronic tuberculosis.