Mycobacterium tuberculosis (Mtb) is a highly successful human pathogen, representing the leading bacterial cause of death worldwide. Mtb infects macrophages and it adapts to the hostile intracellular milieu of this cell by exploiting the plasticity of its central carbon metabolism machinery. While several studies have detailed the bacterial adaptations that accompany infection, it is still unclear whether this process also involves engagement with host metabolic pathways. We therefore profiled the kinetic flux of host cell metabolites in macrophages that were infected with differently virulent Mtb strains. Interestingly, we found that Mtb pathogenicity was indeed intimately linked to its capacity to regulate host cell metabolism. A unique subset of host pathways was targeted so as to integrate the glycolytic threshold governing macrophage viability with mechanisms ensuring intracellular bacterial survival. Perturbation of macrophage glycolytic flux was enforced through pathogen-induced enhancement in glucose uptake, which in turn was also influenced by the extracellular glucose concentration. This observation rationalizes the increased susceptibility of diabetic individuals to TB infection Interestingly, Mtb strains also differed in their capacities to stimulate macrophage glucose uptake. Consequently, the resulting pathology is likely dictated both by the individual's glycemic status, and the nature of the infecting strain.
Vyšlo v časopise: Pathogenicity of Is Expressed by Regulating Metabolic Thresholds of the Host Macrophage. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004265 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004265
1. de CarvalhoLPS, FischerSM, MarreroJ, NathanC, EhrtS, et al. (2010) Metabolomics of Mycobacterium tuberculosis Reveals Compartmentalized Co-Catabolism of Carbon Substrates. Chemistry & biology 17 : 1122–1131.
2. DanielJ, MaamarH, DebC, SirakovaTD, KolattukudyPE (2011) Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS pathogens 7: e1002093.
3. Muñoz-ElíasEJ, McKinneyJD (2005) Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nature medicine 11 : 638–644.
4. PandeyAK, SassettiCM (2008) Mycobacterial persistence requires the utilization of host cholesterol. Proceedings of the National Academy of Sciences 105 : 4376–4380.
5. RohdeKH, VeigaDF, CaldwellS, BalázsiG, RussellDG (2012) Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. PLoS pathogens 8: e1002769.
6. RussellDG, BarryCE, FlynnJL (2010) Tuberculosis: what we don't know can, and does, hurt us. Science 328 : 852–856.
7. RussellDG, CardonaP-J, KimM-J, AllainS, AltareF (2009) Foamy macrophages and the progression of the human tuberculosis granuloma. Nature immunology 10 : 943–948.
8. RussellDG, VanderVenBC, LeeW, AbramovitchRB, KimM-j, et al. (2010) Mycobacterium tuberculosis Wears What It Eats. Cell host & microbe 8 : 68–76.
9. SauerU (2006) Metabolic networks in motion: 13C-based flux analysis. Molecular systems biology 2 : 62.
10. YuanJ, BennettBD, RabinowitzJD (2008) Kinetic flux profiling for quantitation of cellular metabolic fluxes. Nature protocols 3 : 1328–1340.
11. YuanJ, FowlerWU, KimballE, LuW, RabinowitzJD (2006) Kinetic flux profiling of nitrogen assimilation in Escherichia coli. Nature chemical biology 2 : 529–530.
12. CuriR, NewsholmeP, Pithon-CuriT, Pires-de-MeloM, GarciaC, et al. (1999) Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils. Brazilian Journal of Medical and Biological Research 32 : 15–21.
13. SinghV, JamwalS, JainR, VermaP, GokhaleR, et al. (2012) Mycobacterium tuberculosis-Driven Targeted Recalibration of Macrophage Lipid Homeostasis Promotes the Foamy Phenotype. Cell host & microbe 12 : 669–681.
14. IhrlundLS, HernlundE, KhanO, ShoshanMC (2008) 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Molecular oncology 2 : 94–101.
15. PereiraDSA, El-BachaT, KyawN, Dos SantosR, Da-SilvaW, et al. (2009) Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate1. Biochem J 417 : 717–726.
16. Resat H, Petzold L, Pettigrew MF (2009) Kinetic modeling of biological systems. Computational Systems Biology:Springer. pp. 311–335.
17. KumarD, NathL, KamalMA, VarshneyA, JainA, et al. (2010) Genome-wide Analysis of the Host Intracellular Network that Regulates Survival of Mycobacterium tuberculosis. Cell 140 : 731–743.
18. BarghouthiS, EverettK, SpeertDP (1995) Nonopsonic phagocytosis of Pseudomonas aeruginosa requires facilitated transport of D-glucose by macrophages. The Journal of Immunology 154 : 3420–3428.
19. Ida-YonemochiH, NakatomiM, HaradaH, TakataH, BabaO, et al. (2012) Glucose uptake mediated by glucose transporter 1 is essential for early tooth morphogenesis and size determination of murine molars. Developmental biology 363 : 52–61.
20. Rodríguez-EnríquezS, Marín-HernándezA, Gallardo-PérezJC, Moreno-SánchezR (2009) Kinetics of transport and phosphorylation of glucose in cancer cells. Journal of cellular physiology 221 : 552–559.
21. SiessEA, Kientsch-EngelRI, WielandOH (1982) Role of free oxaloacetate in ketogenesis. European Journal of Biochemistry 121 : 493–499.
22. SegalW, BlochH (1956) Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro. Journal of bacteriology 72 : 132.
23. LeeW, VanderVenBC, FaheyRJ, RussellDG (2013) Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. Journal of Biological Chemistry 288 : 6788–6800.
24. Farese JrRV, WaltherTC (2009) Lipid droplets finally get a little RESPECT. Cell 139 : 855–860.
25. D'AvilaH, MeloRC, ParreiraGG, Werneck-BarrosoE, Castro-Faria-NetoHC, et al. (2006) Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: intracellular domains for eicosanoid synthesis in vivo. The Journal of Immunology 176 : 3087–3097.
26. PeyronP, VaubourgeixJ, PoquetY, LevillainF, BotanchC, et al. (2008) Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS pathogens 4: e1000204.
27. ThiamAR, Farese JrRV, WaltherTC (2013) The biophysics and cell biology of lipid droplets. Nature Reviews Molecular Cell Biology 14 : 775–786.
28. LlaveriasG, LacasaD, ViñalsM, Vázquez-CarreraM, SánchezRM, et al. (2004) Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin. Biochemical pharmacology 68 : 155–163.
29. GaoY, LinL-P, ZhuC-H, ChenY, HouY-T, et al. (2006) Research Paper Growth Arrest Induced by C75, A Fatty Acid Synthase Inhibitor, was Partially Modulated by p38 MAPK but Not by p53 In Human Hepatocellular Carcinoma. Cancer biology & therapy 5 : 978–985.
30. KimMJ, WainwrightHC, LocketzM, BekkerLG, WaltherGB, et al. (2010) Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO molecular medicine 2 : 258–274.
31. AronisA, MadarZ, TiroshO (2005) Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774. 2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. Free Radical Biology and Medicine 38 : 1221–1230.
32. AronisA, MadarZ, TiroshO (2008) Lipotoxic effects of triacylglycerols in J774. 2 macrophages. Nutrition 24 : 167–176.
33. BrasaemleDL, RubinB, HartenIA, Gruia-GrayJ, KimmelAR, et al. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. Journal of Biological Chemistry 275 : 38486–38493.
34. HalestrapAP (1978) Pyruvate and ketone-body transport across the mitochondrial membrane. Exchange properties, pH-dependence and mechanism of the carrier. Biochem J 172 : 377–387.
35. HerzigS, RaemyE, MontessuitS, VeutheyJ-L, ZamboniN, et al. (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science 337 : 93–96.
36. BeharSM, DivangahiM, RemoldHG (2010) Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? Nature Reviews Microbiology 8 : 668–674.
37. FratazziC, ArbeitRD, CariniC, RemoldHG (1997) Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. The Journal of Immunology 158 : 4320–4327.
38. LeeJ, HartmanM, KornfeldH (2009) Macrophage apoptosis in tuberculosis. Yonsei medical journal 50 : 1–11.
39. LópezM, SlyLM, LuuY, YoungD, CooperH, et al. (2003) The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2. The Journal of Immunology 170 : 2409–2416.
40. OddoM, RennoT, AttingerA, BakkerT, MacDonaldHR, et al. (1998) Fas ligand-induced apoptosis of infected human macrophages reduces the viability of intracellular Mycobacterium tuberculosis. The Journal of Immunology 160 : 5448–5454.
41. LeeJ, RepasyT, PapavinasasundaramK, SassettiC, KornfeldH (2011) Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages. PloS one 6: e18367.
42. RamakrishnanL (2012) Revisiting the role of the granuloma in tuberculosis. Nature Reviews Immunology 12 : 352–366.
43. ThiEP, LambertzU, ReinerNE (2012) Sleeping with the enemy: how intracellular pathogens cope with a macrophage lifestyle. PLoS pathogens 8: e1002551.
44. BakerMA, HarriesAD, JeonCY, HartJE, KapurA, et al. (2011) The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC medicine 9 : 81.
45. DooleyKE, ChaissonRE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. The Lancet infectious diseases 9 : 737–746.
46. JeonCY, MurrayMB (2008) Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS medicine 5: e152.
47. MartensGW, ArikanMC, LeeJ, RenF, GreinerD, et al. (2007) Tuberculosis susceptibility of diabetic mice. American journal of respiratory cell and molecular biology 37 : 518.
48. VallerskogT, MartensGW, KornfeldH (2010) Diabetic mice display a delayed adaptive immune response to Mycobacterium tuberculosis. The Journal of Immunology 184 : 6275–6282.
49. XavierMN, WinterMG, SpeesAM, den HartighAB, NguyenK, et al. (2013) PPARγ-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated Macrophages. Cell host & microbe 14 : 159–170.
50. PezzuloAA, GutiérrezJ, DuschnerKS, McConnellKS, TaftPJ, et al. (2011) Glucose depletion in the airway surface liquid is essential for sterility of the airways. PloS one 6: e16166.
51. LinJ, LiH, YangM, RenJ, HuangZ, et al. (2013) A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell reports 3 : 200–210.
52. MooreKJ, TabasI (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145 : 341–355.
53. RotaS, RotaS (2005) c yb o osis acterium tubercul M. Acta Med Okayama 59 : 247–251.
54. SheuJ-J, ChiouH-Y, KangJ-H, ChenY-H, LinH-C (2010) Tuberculosis and the Risk of Ischemic Stroke A 3-Year Follow-Up Study. Stroke 41 : 244–249.
55. TabasI (1997) Free cholesterol-induced cytotoxicity: a possible contributing factor to macrophage foam cell necrosis in advanced atherosclerotic lesions. Trends in cardiovascular medicine 7 : 256–263.
56. MungerJ, BennettBD, ParikhA, FengX-J, McArdleJ, et al. (2008) Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature biotechnology 26 : 1179–1186.
57. GuayC, MadirajuSM, AumaisA, JolyÉ, PrentkiM (2007) A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion. Journal of Biological Chemistry 282 : 35657–35665.
58. LiJJ, WangH, TinoJA, RoblJA, HerpinTF, et al. (2007) 2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorganic & medicinal chemistry letters 17 : 3208–3211.
59. HuangC, KuoW, HuangY, LeeT, YuL (2013) Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cells. Cell death & disease 4: e622.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
