“…Activation of murine macrophages with antiinflammatory cytokines, such as IL-4 or IL-13, promotes mTORC1 activation through the PI3K/protein kinase B (Akt) pathway, leading to increased protein synthesis and a switch to anabolic metabolism that is needed to sustain the energy-demanding functions of cell migration, cytokine production and tissue repair. 51,64 Infection of murine macrophages with L. donovani also leads to the activation of mTOR and polarization toward a permissive M2 phenotype, while inhibition of mTORC1 (via rapamycin treatment) limits parasite growth in ex vivo infected macrophages and granuloma development in mice. [67][68][69] Other studies have shown that mTORC1 activates a number of key downstream targets and transcription factors, including HIF-1a, peroxisome proliferator-activated receptor gamma coactivator 1-a, sterol regulatory element-binding protein-1 and PPAR-c, that lead to transcriptional upregulation of proteins involved in glucose uptake, glycolysis, mitochondrial biogenesis, oxidative phosphorylation, and fatty acid and cholesterol biosynthesis that individually or collectively may promote intracellular Leishmania growth.…”