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

Claire B Péan,Pierre Guermonprez,Shinelle Menezes,Martina Pilátová,Brian M Stramer,Karen P Brown,Jessica A Sharrock,Katrin Kierdorf,M Charlotte Maserumule,R Andres Floto,Kévin Bronda,Sharon W S Tan,Mark Schiebler,Marc S Dionne

doi:10.1038/ncomms14642

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.

Highlights

Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood
We have developed a system in which Drosophila are infected with Mycobacterium marinum, which allows us to identify host mechanisms involved in mycobacterial infection[12,13]
We show that haemocyte-derived cytokine signals activate JAK–STAT signalling in haemocytes in the early phases of M. marinum infection

Summary

Introduction

Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. JAK–STAT blockade increased resistance to infection: it prolonged survival of the host, reduced mycobacterial numbers and delayed immune cell death, with similar effects observed in vitro. This effect was associated with overexpression of the autophagy-related gene Atg[2] and not other autophagy genes, in vivo and in vitro. The ability of IL-6 to increase the number of viable intracellular mycobacteria was abolished by inhibition of macrophage triglyceride synthesis Together, these data indicate that loss of a STAT-activating cytokine pathway can reduce survival of intracellular mycobacteria via effects on cellular lipid deposition.

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Conclusion