期刊
CELL REPORTS
卷 30, 期 12, 页码 4052-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.02.098
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资金
- Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) [NORTE-010145-FEDER-000013]
- FEDER funds through COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI) [LISBOA-01-0145-FEDER-007660]
- Fundacao para a Ciencia e Tecnologia (FCT) [SFRH/BD/120127/2016, PD/BDE/127830/2016, SFRH/BD/120371/2016, IF/01147/2013, SFRH/BPD/111100/2015, IF/01390/2014, IF/00735/2014, SFRH/BPD/96176/2013, IF/00021/2014]
- Infect-Era (Project INLEISH)
- Canada Research Chair program
- CWRU/UH Centre for AIDS Research (NIH) [P30 AI036219]
- DBT [BT/In/Infect-eRA/33/BS/2016-2017]
- Fundação para a Ciência e a Tecnologia [PD/BDE/127830/2016, SFRH/BD/120127/2016, SFRH/BD/120371/2016] Funding Source: FCT
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1 alpha 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-1 alpha(-/-) macrophages. L. donovani-infected HIF-1 alpha-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-1 alpha is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.
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