title: Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.
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 delta icl bacteria in interferon-gamma knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the delta 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.
authors.affiliation: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: McKinney
authors.forename: K
authors.initials: K
authors.lastname: Höner zu Bentrup
authors.forename: E J
authors.initials: EJ
authors.lastname: Muñoz-Elías
authors.forename: A
authors.initials: A
authors.lastname: Miczak
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.forename: W T
authors.initials: WT
authors.lastname: Chan
authors.forename: D
authors.initials: D
authors.lastname: Swenson
authors.forename: J C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: W R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: D G
authors.initials: DG
authors.lastname: Russell
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D005227:Fatty Acids / Q000378:metabolism; D007522:Isocitrate Lyase / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D011993:Recombinant Fusion Proteins; C402427:icl protein, Mycobacterium; D007522:Isocitrate Lyase