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. 2021 Sep 23;12:747387. doi: 10.3389/fimmu.2021.747387

Figure 1.

Figure 1

M.tb, M.leprae and M.ulcerans infect macrophages and alter their metabolism. M.tb is primarily sensed by host macrophages through TLR2 and TLR4. Macrophage metabolism shifts towards glycolysis (M1-like), which allows infection control. M.tb has developed strategies to counteract this metabolic switch though induction of miR-21 and IFNβ. M1-like macrophages present a broken TCA cycle, with elevated succinate concentrations that stabilise HIF1α, essential for induction of glycolysis and secretion of pro-inflammatory cytokines such as IL-1β. Itaconate also arises as a consequence of a broken TCA cycle and has multiple immune-regulatory functions, including inhibition of isocitrate lyases Icl1/2. M.tb infection triggers ROS production through NAPDH oxidase. It also promotes increased intracellular lipid content. This results in the development of lipid droplets and the foamy macrophage phenotype, which can be beneficial (i.e. providing cholesterol as nutrient) or detrimental (i.e. secretion of prostaglandins) for the pathogen. M.leprae infection of CD14+ monocytes drives macrophages towards an M2-like phenotype, with a key role for PGL-1. M2-like macrophages rely on oxidative metabolism and are associated with severe lesions. Upon M.leprae infection, macrophages upregulate CD36 and SR-A1 which translates in increased lipid uptake. Lipid droplets and the foamy phenotype have been linked to suppressed mitochondrial function. Furthermore, M.leprae-infected macrophages promote a Treg phenotype when interacting with naïve T cells, together with an impairment of pro-inflammatory cytokine release. Mycolactone released by phagocytozed and extracellular M. ulcerans bacilli diffuses into the cytoplasm of host macrophages and neighboring cells, respectively, gains access to the Sec61 translocon and blocks its activity. An immediate effect of Sec61 blockade by mycolactone is the downregulation of secretory and transmembrane proteins, among which the glucose importer Glut-1, likely resulting in decreased glycolysis. Sustained Sec61 blockade in mycolactone-exposed cells, including macrophages, triggers ER stress responses culminating in apoptosis. Created with BioRender.com.