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The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis.
Mesquita, Inês Ferreira, Carolina Moreira, Diana Kluck, George Eduardo Gabriel Barbosa, Ana Margarida Torrado, Egídio Dinis-Oliveira, Ricardo Jorge Gonçalves, Luís Gafeira Beauparlant, Charles-Joly Droit, Arnaud
Mesquita, Inês
Ferreira, Carolina
Moreira, Diana
Kluck, George Eduardo Gabriel
Barbosa, Ana Margarida
Torrado, Egídio
Dinis-Oliveira, Ricardo Jorge
Gonçalves, Luís Gafeira
Beauparlant, Charles-Joly
Droit, Arnaud
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2020-03-24
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2019-09-02
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Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.
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en
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2211-1247
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Attribution 4.0 International