title: Infection with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs.
abstract: To elucidate the little-known bioenergetic pathways of host immune cells in tuberculosis, a granulomatous disease caused by the intracellular pathogen Mycobacterium tuberculosis, we characterized infected murine lung tissue by transcriptomic profiling and confocal imaging. Transcriptomic analysis revealed changes of host energy metabolism during the course of infection that are characterized by upregulation of key glycolytic enzymes and transporters for glucose uptake, and downregulation of enzymes participating in the tricarboxylic acid cycle and oxidative phosphorylation. Consistent with elevated glycolysis, we also observed upregulation of a transporter for lactate secretion and a V type H(+) -ATPase involved in cytosolic pH homeostasis. Transcription profiling results were corroborated by immunofluorescence microscopy showing increased expression of key glycolytic enzymes in macrophages and T cells in granulomatous lesions. Moreover, we found increased mRNA and protein levels in macrophages and T cells of hypoxia inducible factor 1 alpha (HIF-1α), the regulatory subunit of HIF-1, a master transcriptional regulator. Thus, our findings suggest that immune cells predominantly utilize aerobic glycolysis in response to M. tuberculosis infection. This bioenergetic shift is similar to the Warburg effect, the metabolic signature of cancer cells. Finding immunometabolic changes during M. tuberculosis infection opens the way to new strategies for immunotherapy against tuberculosis.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Shi
authors.affiliation: Knowledge Synthesis Inc. Berkeley, CA, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Salamon
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.affiliation: Trudeau Institute, Saranac Lake, NY, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gennaro
mesh_terms: D000818:Animals; D015415:Biomarkers; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010085:Oxidative Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D059467:Transcriptome; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000378:metabolism* / Q000382:microbiology
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011768:Pyruvate Dehydrogenase Complex; D005947:Glucose