Leishmania infantum modulates host macrophage mitochondrial metabolism by hijacking the SIRT1-AMPK axis.
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.
Parasite Disease Group, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Diana
D
Moreira
Parasite Disease Group, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; CNRS FRE 3636, Université Paris Descartes, Paris, France.
Vasco
V
Rodrigues
Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
Maria
M
Abengozar
Unidad Metabolómica, Interacciones y Bioanálisis (UMIB), Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
Luis
L
Rivas
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
Eduardo
E
Rial
CNRS FRE 3636, Université Paris Descartes, Paris, France.
Mireille
M
Laforge
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
Xiaoling
X
Li
INSERM U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Marc
M
Foretz
INSERM U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Benoit
B
Viollet
CNRS FRE 3636, Université Paris Descartes, Paris, France; Université Laval, Centre de Recherche du CHU de Québec, Québec, Canada.
Jérôme
J
Estaquier
Parasite Disease Group, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Anabela
A
Cordeiro da Silva
Parasite Disease Group, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Ricardo
R
Silvestre
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000276:immunology; D057131:Immune Evasion; D018314:Leishmania infantum / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology*; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
D051275:Glucose Transporter Type 4; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1