Portal de investigação
The Absence of HIF-1a Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Mesquita, I
- Ferreira, C
- Moreira, D
- Kluck, GEG
- Barbosa, AM
- Torrado, E
- Gonçalves, LG
- Beauparlant, CJ
- Droit, A
- Berod, L
- Sparwasser, T
- Bodhale, N
- Saha, B
- Rodrigues, F
- Cunha, C
- Carvalho, A
- Castro, AG
- Estaquier, J
- Silvestre, R
Unidades de investigação
Abstract
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.
Dados da publicação
- ISSN/ISSNe:
- 2211-1247, 2211-1247
- Tipo:
- Article
- Páginas:
- 4052-4052
- Link para outro recurso:
- www.scopus.com
Cell Reports Cell Press
Citações Recebidas na Web of Science: 29
Citações Recebidas na Scopus: 33
Documentos
- Não há documentos
Filiações
Keywords
- FATTY-ACID SYNTHASE; HYPOXIA-INDUCIBLE FACTOR-1; LIPID DROPLETS; TRANSCRIPTION FACTORS; ORGAN INJURY; INHIBITION; METABOLISM; EXPRESSION; GENE; ACCUMULATION
Campos de estudo
Financiamento
Proyectos asociados
Research into toxicological mechanisms of tramadol and tapentadol: clinical and forensic aspects.
Investigador Principal: Ricardo Jorge Dinis Oliveira
Estudo Clínico Académico . 2019
Citar a publicação
Mesquita I,Ferreira C,Moreira D,Kluck G,Barbosa AM,Torrado E,Dinis R,Gonçalves LG,Beauparlant CJ,Droit A,Berod L,Sparwasser T,Bodhale N,Saha B,Rodrigues F,Cunha C,Carvalho A,Castro AG,Estaquier J,Silvestre R. The Absence of HIF-1a Increases Susceptibility to <i>Leishmania donovani</i> Infection via Activation of BNIP3/mTOR/SREBP-1c Axis. Cell Rep. 2020. 30. (12):p. 4052-4052. IF:9,423. (1).
