Mycobacterium tuberculosis Modulates the Metabolism of Alternatively Activated Macrophages to Promote Foam Cell Formation and Intracellular Survival

The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM). Indeed, FM are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate if distinct macrophage activation states exposed to a tuberculosis-associated microenvironment can accumulate LBs, and its impact on the control of infection. We showed that signal transducer and activator of transcription 6 (STAT6) activation in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the {beta}-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. We demonstrated that inhibition of the lipolytic activity or of the FAO drives M(IL-4) macrophages into FM. Also, exhibiting a predominant FAO metabolism, mouse alveolar macrophages are less prone to become FM compared to bone marrow derived-macrophages. Upon Mtb infection, M(IL-4) macrophages are metabolically re-programmed towards the aerobic glycolytic pathway and evolve towards a foamy phenotype, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1)-induced glycolytic pathway. In conclusion, our results demonstrate a role for STAT6-driven FAO in preventing FM differentiation, and reveal an extraordinary capacity by Mtb to rewire metabolic pathways in human macrophages and induce the favorable FM. IMPORTANCETuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). While its treatment was already standardized, TB remains one of the top 10 death causes worldwide. A major problem is the efficient adaptation of Mtb to the macrophage intracellular milieu, which includes deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM) which are favorable to Mtb. A critical aspect of our work is the use of tuberculous pleural effusions (TB-PE) -- human-derived biological fluid capable of mimicking the complex microenvironment of the lung cavity upon Mtb infection -- to study the FM metabolic modulation. We revealed how the STAT6 transcription factor prevents FM formation induced by PE-TB, and how Mtb counteracts it by activating another transcription factor, HIF-1, to re-establish FM. This study provides key insights in host lipid metabolism, macrophage biology and pathogen subversion strategies, to be exploited for prevention and therapeutic purposes in infectious diseases.