title: HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis.
abstract: The cytokine IFN-γ coordinates macrophage activation and is essential for control of pathogens, including Mycobacterium tuberculosis However, the mechanisms by which IFN-γ controls M. tuberculosis infection are only partially understood. In this study, we show that the transcription factor hypoxia-inducible factor-1α (HIF-1α) is an essential mediator of IFN-γ-dependent control of M. tuberculosis infection both in vitro and in vivo. M. tuberculosis infection of IFN-γ-activated macrophages results in a synergistic increase in HIF-1α protein levels. This increase in HIF-1α levels is functionally important, as macrophages lacking HIF-1α are defective for IFN-γ-dependent control of infection. RNA-sequencing demonstrates that HIF-1α regulates nearly one-half of all IFN-γ-inducible genes during infection of macrophages. In particular, HIF-1α regulates production of important immune effectors, including inflammatory cytokines and chemokines, eicosanoids, and NO. In addition, we find that during infection HIF-1α coordinates a metabolic shift to aerobic glycolysis in IFN-γ-activated macrophages. We find that this enhanced glycolytic flux is crucial for IFN-γ-dependent control of infection in macrophages. Furthermore, we identify a positive feedback loop between HIF-1α and aerobic glycolysis that amplifies macrophage activation. Finally, we demonstrate that HIF-1α is crucial for control of infection in vivo as mice lacking HIF-1α in the myeloid lineage are strikingly susceptible to infection and exhibit defective production of inflammatory cytokines and microbicidal effectors. In conclusion, we have identified HIF-1α as a novel regulator of IFN-γ-dependent immunity that coordinates an immunometabolic program essential for control of M. tuberculosis infection in vitro and in vivo.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720;
authors.forename: Jonathan
authors.identifier: 0000-0002-0759-7220
authors.initials: J
authors.lastname: Braverman
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720; and.
authors.forename: Kimberly M
authors.identifier: 0000-0002-4011-2440
authors.initials: KM
authors.lastname: Sogi
authors.affiliation: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Daniel
authors.initials: D
authors.lastname: Benjamin
authors.affiliation: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Daniel K
authors.identifier: 0000-0003-1614-8360
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720; and sastanley@berkeley.edu.
authors.forename: Sarah A
authors.identifier: 0000-0002-4182-9048
authors.initials: SA
authors.lastname: Stanley
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D006019:Glycolysis / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis; D016133:Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014376:Tuberculosis / Q000276:immunology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007371:Interferon-gamma