Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis

English version České info

Leishmania infantum, a causative agent of visceral leishmaniasis, is able to infect host macrophages and modulate a myriad of signalling pathways that contributes to the disease outcome. In order to survive, L. infantum must compete with the host for the same metabolic resources, however scarce attention has been dedicated to clarify the potential interference of the parasite with the host metabolic pathways and its impact for the infection outcome. We analysed the macrophage metabolic alterations induced by L. infantum focusing on host energetic players exploited by the parasite. We describe that L. infantum induced a metabolic switch from an early aerobic glycolytic environment to a later mitochondrial metabolism. In this process, L. infantum modulates important energetic sensors of the host, such as the SIRT1-LKB1-AMPK axis. This triad is important for the recovery of the host energetic status and also for the parasite survival. With this work, we demonstrate that the host SIRT1-LKB1-AMPK axis has a crucial impact on the parasite survival in vitro and in vivo.

Vyšlo v časopise: Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004684
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004684

Souhrn

Zdroje

1. Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366 : 1561–1577. 16257344

2. Rodrigues V, Cordeiro-da-Silva A, Laforge M, Ouaissi A, Akharid K, et al. (2014) Impairment of T cell function in parasitic infections. PLoS Negl Trop Dis 8: e2567. doi: 10.1371/journal.pntd.0002567 24551250

3. Rodrigues V, Cordeiro-da-Silva A, Laforge M, Ouaissi A, Silvestre R, et al. (2012) Modulation of mammalian apoptotic pathways by intracellular protozoan parasites. Cell Microbiol 14 : 325–333. doi: 10.1111/j.1462-5822.2011.01737.x 22168464

4. Estaquier J, Vallette F, Vayssiere JL, Mignotte B (2012) The mitochondrial pathways of apoptosis. Adv Exp Med Biol 942 : 157–183. doi: 10.1007/978-94-007-2869-1_7 22399422

5. Caradonna KL, Engel JC, Jacobi D, Lee CH, Burleigh BA (2013) Host metabolism regulates intracellular growth of Trypanosoma cruzi. Cell Host Microbe 13 : 108–117. doi: 10.1016/j.chom.2012.11.011 23332160

6. Brunton J, Steele S, Ziehr B, Moorman N, Kawula T (2013) Feeding uninvited guests: mTOR and AMPK set the table for intracellular pathogens. PLoS Pathog 9: e1003552. doi: 10.1371/journal.ppat.1003552 24098109

7. Mankouri J, Harris M (2011) Viruses and the fuel sensor: the emerging link between AMPK and virus replication. Rev Med Virol 21 : 205–212. doi: 10.1002/rmv.687 21538667

8. Viollet B, Horman S, Leclerc J, Lantier L, Foretz M, et al. (2010) AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol 45 : 276–295. doi: 10.3109/10409238.2010.488215 20522000

9. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, et al. (2003) Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2 : 28. 14511394

10. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, et al. (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13 : 2004–2008. 14614828

11. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, et al. (2005) Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2 : 21–33. 16054096

12. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, et al. (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2 : 9–19. 16054095

13. Verdin E, Hirschey MD, Finley LW, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35 : 669–675. doi: 10.1016/j.tibs.2010.07.003 20863707

14. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, et al. (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298: E751–760. doi: 10.1152/ajpendo.00745.2009 20103737

15. Austin S, St-Pierre J (2012) PGC1alpha and mitochondrial metabolism—emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 125 : 4963–4971. doi: 10.1242/jcs.113662 23277535

16. Seifert EL, Caron AZ, Morin K, Coulombe J, He XH, et al. (2012) SirT1 catalytic activity is required for male fertility and metabolic homeostasis in mice. FASEB J 26 : 555–566. doi: 10.1096/fj.11-193979 22006156

17. McConville MJ, de Souza D, Saunders E, Likic VA, Naderer T (2007) Living in a phagolysosome; metabolism of Leishmania amastigotes. Trends Parasitol 23 : 368–375. 17606406

18. Rabhi I, Rabhi S, Ben-Othman R, Rasche A, Daskalaki A, et al. (2012) Transcriptomic signature of Leishmania infected mice macrophages: a metabolic point of view. PLoS Negl Trop Dis 6: e1763. doi: 10.1371/journal.pntd.0001763 22928052

19. Jaramillo M, Gomez MA, Larsson O, Shio MT, Topisirovic I, et al. (2011) Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe 9 : 331–341. doi: 10.1016/j.chom.2011.03.008 21501832

20. Smith SM, Snyder IS (1975) Effect of lipopolysaccharide and lipid A on mouse liver pyruvate kinase activity. Infect Immun 12 : 993–998. 1104489

21. Sajic T, Hainard A, Scherl A, Wohlwend A, Negro F, et al. (2013) STAT6 promotes bi-directional modulation of PKM2 in liver and adipose inflammatory cells in rosiglitazone-treated mice. Sci Rep 3 : 2350. doi: 10.1038/srep02350 23917405

22. Yang L, Xie M, Yang M, Yu Y, Zhu S, et al. (2014) PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 5 : 4436. doi: 10.1038/ncomms5436 25019241

23. Carvalho LP, Pearce EJ, Scott P (2008) Functional dichotomy of dendritic cells following interaction with Leishmania braziliensis: infected cells produce high levels of TNF-alpha, whereas bystander dendritic cells are activated to promote T cell responses. J Immunol 181 : 6473–6480. 18941238

24. Resende M, Moreira D, Augusto J, Cunha J, Neves B, et al. (2013) Leishmania-infected MHC class IIhigh dendritic cells polarize CD4+ T cells toward a nonprotective T-bet+ IFN-gamma+ IL-10+ phenotype. J Immunol 191 : 262–273. doi: 10.4049/jimmunol.1203518 23729437

25. Cronemberger-Andrade A, Aragao-Franca L, de Araujo CF, Rocha VJ, Borges-Silva Mda C, et al. (2014) Extracellular vesicles from Leishmania-infected macrophages confer an anti-infection cytokine-production profile to naive macrophages. PLoS Negl Trop Dis 8: e3161. doi: 10.1371/journal.pntd.0003161 25232947

26. Sakamoto T, Seiki M (2010) A membrane protease regulates energy production in macrophages by activating hypoxia-inducible factor-1 via a non-proteolytic mechanism. J Biol Chem 285 : 29951–29964. doi: 10.1074/jbc.M110.132704 20663879

27. Garedew A, Henderson SO, Moncada S (2010) Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Differ 17 : 1540–1550. doi: 10.1038/cdd.2010.27 20339378

28. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458 : 1056–1060. doi: 10.1038/nature07813 19262508

29. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, et al. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434 : 113–118. 15744310

30. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, et al. (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303 : 2011–2015. 14976264

31. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, et al. (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9 : 327–338. doi: 10.1016/j.cmet.2009.02.006 19356714

32. Canto C, Auwerx J (2009) PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20 : 98–105. doi: 10.1097/MOL.0b013e328328d0a4 19276888

33. Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283 : 27628–27635. doi: 10.1074/jbc.M805711200 18687677

34. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, et al. (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283 : 20015–20026. doi: 10.1074/jbc.M802187200 18482975

35. Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, et al. (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 14 : 661–673. doi: 10.1016/j.devcel.2008.02.004 18477450

36. Gazanion E, Garcia D, Silvestre R, Gerard C, Guichou JF, et al. (2011) The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation. Mol Microbiol 82 : 21–38. doi: 10.1111/j.1365-2958.2011.07799.x 21819459

37. Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404 : 1–13. 17447894

38. Hassani K, Olivier M (2013) Immunomodulatory impact of leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis. PLoS Negl Trop Dis 7: e2185. doi: 10.1371/journal.pntd.0002185 23658846

39. Santarem N, Racine G, Silvestre R, Cordeiro-da-Silva A, Ouellette M (2013) Exoproteome dynamics in Leishmania infantum. J Proteomics 84 : 106–118. doi: 10.1016/j.jprot.2013.03.012 23558030

40. Shio MT, Hassani K, Isnard A, Ralph B, Contreras I, et al. (2012) Host cell signalling and leishmania mechanisms of evasion. J Trop Med 2012 : 819512. doi: 10.1155/2012/819512 22131998

41. Akarid K, Arnoult D, Micic-Polianski J, Sif J, Estaquier J, et al. (2004) Leishmania major-mediated prevention of programmed cell death induction in infected macrophages is associated with the repression of mitochondrial release of cytochrome c. J Leukoc Biol 76 : 95–103. 15075349

42. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3 : 177–185. 16517405

43. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3 : 187–197. 16517406

44. Moreira D, Santarem N, Loureiro I, Tavares J, Silva AM, et al. (2012) Impact of continuous axenic cultivation in Leishmania infantum virulence. PLoS Negl Trop Dis 6: e1469. doi: 10.1371/journal.pntd.0001469 22292094

45. Resende LA, Roatt BM, Aguiar-Soares RD, Viana KF, Mendonca LZ, et al. (2013) Cytokine and nitric oxide patterns in dogs immunized with LBSap vaccine, before and after experimental challenge with Leishmania chagasi plus saliva of Lutzomyia longipalpis. Vet Parasitol 198 : 371–381. doi: 10.1016/j.vetpar.2013.09.011 24129068

46. Cunha J, Carrillo E, Sanchez C, Cruz I, Moreno J, et al. (2013) Characterization of the biology and infectivity of Leishmania infantum viscerotropic and dermotropic strains isolated from HIV+ and HIV -⁠ patients in the murine model of visceral leishmaniasis. Parasit Vectors 6 : 122. doi: 10.1186/1756-3305-6-122 23622683

47. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, et al. (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141 : 280–289. doi: 10.1016/j.cell.2010.02.026 20403324

48. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, et al. (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120 : 2355–2369. doi: 10.1172/JCI40671 20577053