TY - JOUR
T1 - Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis
AU - Moreira, Diana
AU - Rodrigues, Vasco
AU - Abengozar, Maria
AU - Rivas, Luis
AU - Rial, Eduardo
AU - Laforge, Mireille
AU - Li, Xiaoling
AU - Foretz, Marc
AU - Viollet, Benoit
AU - Estaquier, Jérôme
AU - Cordeiro da Silva, Anabela
AU - Silvestre, Ricardo
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84926480675&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926480675&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1004684
DO - 10.1371/journal.ppat.1004684
M3 - Article
C2 - 25738568
AN - SCOPUS:84926480675
SN - 1553-7366
VL - 11
SP - 1
EP - 24
JO - PLoS pathogens
JF - PLoS pathogens
IS - 3
M1 - e1004684
ER -