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Nat Commun. 2017 Mar 6;8:14642. doi: 10.1038/ncomms14642.

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.

Author information

1
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.
2
Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge CB2 0QH, UK.
3
Centre for Molecular and Cellular Biology of Inflammation, School of Medicine, King's College London, London SE1 1UL, UK.
4
Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge CB23 3RE, UK.
5
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.

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.

PMID:
28262681
PMCID:
PMC5343520
DOI:
10.1038/ncomms14642
[Indexed for MEDLINE]
Free PMC Article

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