title: Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.
abstract: Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum, mycobacterium-induced STAT activity triggered by unpaired-family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila.
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, and Department of Life Sciences, Imperial College London, Ground Floor, Flowers Building, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Claire B
authors.initials: CB
authors.lastname: Péan
authors.affiliation: Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Schiebler
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, School of Medicine, King's College London, London SE1 1UL, UK.
authors.forename: Sharon W S
authors.initials: SW
authors.lastname: Tan
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, and Department of Life Sciences, Imperial College London, Ground Floor, Flowers Building, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Sharrock
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, and Department of Life Sciences, Imperial College London, Ground Floor, Flowers Building, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.affiliation: Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.|Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge CB23 3RE, UK.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Brown
authors.affiliation: Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.
authors.forename: M Charlotte
authors.initials: MC
authors.lastname: Maserumule
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, School of Medicine, King's College London, London SE1 1UL, UK.
authors.forename: Shinelle
authors.initials: S
authors.lastname: Menezes
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Pilátová
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, School of Medicine, King's College London, London SE1 1UL, UK.
authors.forename: Kévin
authors.initials: K
authors.lastname: Bronda
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, School of Medicine, King's College London, London SE1 1UL, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Guermonprez
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stramer
authors.affiliation: Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.|Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge CB23 3RE, UK.
authors.forename: R
authors.initials: R
authors.lastname: Andres Floto
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, and Department of Life Sciences, Imperial College London, Ground Floor, Flowers Building, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Marc S
authors.identifier: 0000-0002-8283-1750
authors.initials: MS
authors.lastname: Dionne
mesh_terms: D000818:Animals; D000071183:Autophagy-Related Proteins / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000276:immunology; D004330:Drosophila; D029721:Drosophila Proteins / Q000276:immunology* / Q000378:metabolism; D006434:Hemocytes; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D009164:Mycobacterium Infections / Q000276:immunology* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000276:immunology / Q000472:pathogenicity; D019910:Mycobacterium marinum / Q000276:immunology / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D061251:Primary Cell Culture; D050791:STAT Transcription Factors / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014280:Triglycerides / Q000276:immunology / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000276:immunology* / Q000378:metabolism; D014774:Virulence
chemical_list: C572313:ATG2B protein, human; C550900:Atg2 protein, Drosophila; D000071183:Autophagy-Related Proteins; D029721:Drosophila Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D050791:STAT Transcription Factors; D014280:Triglycerides; D033921:Vesicular Transport Proteins