2020
DOI: 10.1016/j.celrep.2020.02.098
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The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis

Abstract: Highlights d HIF-1a is a protective factor against Leishmania donovani infection d In absence of HIF-1a, lipogenesis is induced via BNIP3/ mTOR/SREBP-1c modulation d Blockage of lipogenesis reverts HIF-1a-associated Leishmania susceptibility d HIF1A polymorphism correlates with susceptibility to infection

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Cited by 38 publications
(43 citation statements)
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References 91 publications
(101 reference statements)
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“…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. 51,64 Remarkably, constitutive mTORC1 activation in murine macrophages (via TSC2 knockdown) resulted in spontaneous formation of macrophage-rich granulomas in a murine model for sarcoidosis, 66 suggesting that activation of mTORC1 by L. donovani may stimulate this innate host immune response.…”
Section: Mtor Signaling and Regulation Of Leishmania Growthmentioning
confidence: 99%
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“…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. 51,64 Remarkably, constitutive mTORC1 activation in murine macrophages (via TSC2 knockdown) resulted in spontaneous formation of macrophage-rich granulomas in a murine model for sarcoidosis, 66 suggesting that activation of mTORC1 by L. donovani may stimulate this innate host immune response.…”
Section: Mtor Signaling and Regulation Of Leishmania Growthmentioning
confidence: 99%
“…69 Interestingly, the mTORC1-induced increase in fatty acid synthesis in L. donovani-infected murine macrophage was exacerbated following genetic loss of HIF-1a. 69 HIF-1a is activated by mTORC1 and may redirect the metabolic switch of infected macrophages toward a more glycolytic/M1-like phenotype. Consistent with this possibility, the permissiveness of macrophages isolated from different mouse strains to L. donovani infection was inversely related to HIF-1a expression.…”
Section: Mtor Signaling and Regulation Of Leishmania Growthmentioning
confidence: 99%
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“…In human macrophages, reduced SREBP2 activity was associated with reduced production of the chemokine CCL17 [ 57 ]. Aberrant activation of SREBP signalling has been linked to impaired macrophage responses against Leichmania donovani parasites due to increased fatty acid synthesis and accumulation [ 58 ]. Therefore, there is abundant evidence that oxysterol-SREBP signalling is important for macrophage responses but whether this signalling axis also has a role in the control of other myeloid lineages remains to be determined.…”
Section: Oxysterols and Immune Functionmentioning
confidence: 99%