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.

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…IL‐6 treatment potentiated the increase in intracellular LDs driven by M. bovis BCG infection and promoted intracellular mycobacterial survival probably by enhancing bacterial access to host triglycerides. These effects were dependent on DGAT1 activation, and DGAT‐1 inhibition abolished the ability of mycobacteria to drive LD accumulation and eliminated the ability of IL‐6 to promote mycobacterial survival …”

“…These effects were dependent on DGAT1 activation, and DGAT-1 inhibition abolished the ability of mycobacteria to drive LD accumulation and eliminated the ability of IL-6 to promote mycobacterial survival. 88…”

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

“…Infection of adult flies with the intracellular bacterial pathogen Mycobacterium marinarum leads to a progressive depletion of whole-animal triglyceride stores concomitant with lipid accumulation in phagocytes that harbor mycobacteria (Dionne et al, 2006;Péan et al, 2017).…”

When Dicty Met Myco, a (Not So) Romantic Story about One Amoeba and Its Intracellular Pathogen

“…Moreover, with the help of an in vitro dormancy model, it was proposed that M. bovis BCG uses the TAGs released from ILIs as an energy source during reactivation from dormancy (Low et al, 2009 ). In addition, when the synthesis of TAGs is inhibited in Drosophila melanogaster , the accumulation of host LDs induced by M. marinum infection is also prevented, and the mycobacteria-LDs association, as well as the number of intracellular viable M. marinum , are reduced (Pean et al, 2017 ). Furthermore, ILI-rich mycobacteria have been shown to be more tolerant to rifampicin, isoniazid, ethambutol, and ciprofloxacin (Hammond et al, 2015 ).…”