期刊
PLOS PATHOGENS
卷 11, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1004684
关键词
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资金
- FEDER funds through the Operational Competitiveness Programme - COMPETE
- National Funds through FCT - Fundacao para a Ciencia e a Tecnologia [FCOMP-01-0124-FEDER-011054 (PTDC/SAU-FCF/100749/2008), PTDC/BIA-MIC/118644/2010]
- European Community [602773]
- ISCIII-Subdireccion General de Redes y Centros de Investigacion Cooperativa-FEDER [RICET RD12/0018/0007]
- Spanish Ministerio de Economia y Competitividad [SAF2010-20256]
- ANR grant (LEISH-APO, France)
- Partenariat Hubert Curien (PHC) (program Volubilis) [MA/11/262]
- Canada Research Chair programme
- ANR
- Programa Ciencia - Programa Operacional Potencial Humano POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico
- Fundo Social Europeu and National funding from Ministry of Science, Technology and Higher Education (MCTES)
- [SFRH/BD/91543/2012]
- [SFRH/BD/64064/2009]
- [PN de I+D+I 2008-2011]
- [PI12-02706]
- [VI PN de I+D+I 2008-2011]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-FCF/100749/2008, PTDC/BIA-MIC/118644/2010] Funding Source: FCT
Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis.
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