The Absence of HIF-1 alpha Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Mesquita, I (Author) Other; Ferreira, C (Author) Other; Moreira, D (Author) Other; Gabriel Kluck, GEG (Author) Other; Barbosa, AM (Author) Other; Torrado, E (Author) Other; Ricardo Jorge Dinis Oliveira (Author) FMUP; Goncalves, LG (Author) Other; Beauparlant, CJ (Author) Other; Droit, A (Author) Other; Berod, L (Author) Other; Sparwasser, T (Author) Other; Bodhale, N (Author) Other; Saha, B (Author) Other; Rodrigues, F (Author) Other; Cunha, C (Author) Other; Carvalho, A (Author) Other; Castro, AG (Author) Other; Estaquier, J (Author) Other; Silvestre, R (Author) Other

Journal

Title: Cell Reports

Vol. 30

Pages: 4052-+

ISSN: 2211-1247

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 20 Citations

Scopus - 21 Citations

Other information

Authenticus ID: P-00R-XKK

DOI: 10.1016/j.celrep.2020.02.098

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 20