Dengue virus reduces AGPAT1 expression to alter phospholipids and enhance infection in Aedes aegypti

English version

Autoři: Thomas Vial ^aff001; Wei-Lian Tan ^aff002; Benjamin Wong Wei Xiang ^aff002; Dorothée Missé ^aff003; Eric Deharo ^aff001; Guillaume Marti ^aff001; Julien Pompon ^aff002
Působiště autorů: UMR 152 PHARMADEV-IRD, Université Paul Sabatier-Toulouse 3, Toulouse, France ^aff001; Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore ^aff002; MIVEGEC, IRD, CNRS, Univ. Montpellier, Montpellier, France ^aff003
Vyšlo v časopise: Dengue virus reduces AGPAT1 expression to alter phospholipids and enhance infection in Aedes aegypti. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008199
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1008199

Souhrn

More than half of the world population is at risk of dengue virus (DENV) infection because of the global distribution of its mosquito vectors. DENV is an envelope virus that relies on host lipid membranes for its life-cycle. Here, we characterized how DENV hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography–high resolution mass spectrometry (LC-HRMS) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. We revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. We phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. We showed that DENV infection decreased AGPAT1, but did not alter AGPAT2 expression in cells, midguts and mosquitoes. Depletion of either AGPAT1 or AGPAT2 increased aminophospholipids and partially recapitulated DENV-induced reconfiguration before infection in vitro. However, only AGPAT1 depletion promoted infection by maintaining high aminophospholipid concentrations. In mosquitoes, AGPAT1 depletion also partially recapitulated DENV-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. These results indicate that DENV inhibition of AGPAT1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito’s early DENV cycle. Furthermore, in AGPAT1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. Our study suggests that DENV regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting AGPAT1 expression to increase aminophospholipid availability for virus multiplication.

Klíčová slova:

Lipids – Phospholipids – Blood – Dengue virus – Metabolomics – Guide RNA – Cell metabolism – Mosquitoes

Zdroje

1. Gubler DJ. The Global Emergence/Resurgence of Arboviral Diseases As Public Health Problems. Arch Med Res. 2002;33: 330–342. doi: 10.1016/s0188-4409(02)00378-8 12234522

2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496: 504–507. doi: 10.1038/nature12060 23563266

3. Capeding MR, Tran NH, Hadinegoro SRS, Ismail HIHM, Chotpitayasunondh T, Chua MN, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. The Lancet. 2014;384: 1358–1365. doi: 10.1016/S0140-6736(14)61060-6

4. WHO. Dengue vaccine: WHO position paper–September 2018. 2018. Available: http://apps.who.int/iris/bitstream/handle/10665/274315/WER9336.pdf?ua=1

5. WHO SEARO, Regional Office for South-East Asia. Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever. New Delhi, India: World Health Organization Regional Office for South-East Asia; 2011. Available: http://www.searo.who.int/entity/vector_borne_tropical_diseases/documents/SEAROTPS60/en/

6. Liu N. Insecticide Resistance in Mosquitoes: Impact, Mechanisms, and Research Directions. Annu Rev Entomol. 2015;60: 537–559. doi: 10.1146/annurev-ento-010814-020828 25564745

7. Villareal VA, Rodgers MA, Costello DA, Yang PL. Targeting host lipid synthesis and metabolism to inhibit dengue and hepatitis C viruses. Antiviral Res. 2015;124: 110–121. doi: 10.1016/j.antiviral.2015.10.013 26526588

8. Pando-Robles V, Oses-Prieto JA, Rodríguez-Gandarilla M, Meneses-Romero E, Burlingame AL, Batista CVF. Quantitative proteomic analysis of Huh-7 cells infected with Dengue virus by label-free LC–MS. J Proteomics. 2014;111: 16–29. doi: 10.1016/j.jprot.2014.06.029 25009145

9. Allonso D, Andrade IS, Conde JN, Coelho DR, Rocha DCP, da Silva ML, et al. Dengue Virus NS1 Protein Modulates Cellular Energy Metabolism by Increasing Glyceraldehyde-3-Phosphate Dehydrogenase Activity. J Virol. 2015;89: 11871–11883. doi: 10.1128/JVI.01342-15 26378175

10. Fontaine KA, Sanchez EL, Camarda R, Lagunoff M. Dengue Virus Induces and Requires Glycolysis for Optimal Replication. Sandri-Goldin RM, editor. J Virol. 2015;89: 2358–2366. doi: 10.1128/JVI.02309-14 25505078

11. Birungi G, Chen SM, Loy BP, Ng ML, Li SFY. Metabolomics Approach for Investigation of Effects of Dengue Virus Infection Using the EA.hy926 Cell Line. J Proteome Res. 2010;9: 6523–6534. doi: 10.1021/pr100727m 20954703

12. El-Bacha T, Midlej V, Pereira da Silva AP, Silva da Costa L, Benchimol M, Galina A, et al. Mitochondrial and bioenergetic dysfunction in human hepatic cells infected with dengue 2 virus. Biochim Biophys Acta BBA—Mol Basis Dis. 2007;1772: 1158–1166. doi: 10.1016/j.bbadis.2007.08.003 17964123

13. Heaton NS, Randall G. Dengue Virus-Induced Autophagy Regulates Lipid Metabolism. Cell Host Microbe. 2010;8: 422–432. doi: 10.1016/j.chom.2010.10.006 21075353

14. Diop F, Vial T, Ferraris P, Wichit S, Bengue M, Hamel R, et al. Zika virus infection modulates the metabolomic profile of microglial cells. PLOS ONE. 2018;13: e0206093. doi: 10.1371/journal.pone.0206093 30359409

15. Cui L, Lee YH, Kumar Y, Xu F, Lu K, Ooi EE, et al. Serum Metabolome and Lipidome Changes in Adult Patients with Primary Dengue Infection. Michael SF, editor. PLoS Negl Trop Dis. 2013;7: e2373. doi: 10.1371/journal.pntd.0002373 23967362

16. Martín-Acebes MA, Vázquez-Calvo Á, Saiz J-C. Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses. Prog Lipid Res. 2016;64: 123–137. doi: 10.1016/j.plipres.2016.09.005 27702593

17. Perera R, Riley C, Isaac G, Hopf-Jannasch AS, Moore RJ, Weitz KW, et al. Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells. PLoS Pathog. 2012;8. doi: 10.1371/journal.ppat.1002584 22457619

18. Chotiwan N, Andre BG, Sanchez-Vargas I, Islam MN, Grabowski JM, Hopf-Jannasch A, et al. Dynamic remodeling of lipids coincides with dengue virus replication in the midgut of Aedes aegypti mosquitoes. PLOS Pathog. 2018;14: e1006853. doi: 10.1371/journal.ppat.1006853 29447265

19. Xi Z, Ramirez JL, Dimopoulos G. The Aedes aegypti Toll Pathway Controls Dengue Virus Infection. PLoS Pathog. 2008;4. doi: 10.1371/journal.ppat.1000098 18604274

20. Martín-Acebes MA, Blázquez A-B, Jiménez de Oya N, Escribano-Romero E, Saiz J-C. West Nile Virus Replication Requires Fatty Acid Synthesis but Is Independent on Phosphatidylinositol-4-Phosphate Lipids. Wang T, editor. PLoS ONE. 2011;6: e24970. doi: 10.1371/journal.pone.0024970 21949814

21. Heaton NS, Perera R, Berger KL, Khadka S, LaCount DJ, Kuhn RJ, et al. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A. 2010;107: 17345–17350. doi: 10.1073/pnas.1010811107 20855599

22. Fagone P, Jackowski S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res. 2009;50: S311–S316. doi: 10.1194/jlr.R800049-JLR200 18952570

23. Takeuchi K, Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis., Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab Am J Physiol—Endocrinol Metab. 2009;296, 296: E1195, E1195–209. doi: 10.1152/ajpendo.90958.2008 19336658

24. Athenstaedt K, Daum G. Phosphatidic acid, a key intermediate in lipid metabolism. Eur J Biochem. 1999;266: 1–16. doi: 10.1046/j.1432-1327.1999.00822.x 10542045

25. Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The Endoplasmic Reticulum Provides the Membrane Platform for Biogenesis of the Flavivirus Replication Complex. J Virol. 2010;84: 10438–10447. doi: 10.1128/JVI.00986-10 20686019

26. Aktepe TE, Mackenzie JM. Shaping the flavivirus replication complex: It is curvaceous! Cell Microbiol. 2018;20: e12884. doi: 10.1111/cmi.12884 29933527

27. Salazar MI, Richardson JH, Sánchez-Vargas I, Olson KE, Beaty BJ. Dengue virus type 2: replication and tropisms in orally infected Aedes aegypti mosquitoes. BMC Microbiol. 2007;7: 9. doi: 10.1186/1471-2180-7-9 17263893

28. Barrows Nicholas J., Mariano A. Garcia-Blanco. Biochemistry and Molecular Biology of Flaviviruses. Chem Rev. 2018;118: 4448–4482. doi: 10.1021/acs.chemrev.7b00719 29652486

29. Tsugawa H. Advances in computational metabolomics and databases deepen the understanding of metabolisms. Curr Opin Biotechnol. 2018;54: 10–17. doi: 10.1016/j.copbio.2018.01.008 29413746

30. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9: 112–124. doi: 10.1038/nrm2330 18216768

31. Vance JE. Phospholipid Synthesis and Transport in Mammalian Cells. Traffic. 2015;16: 1–18. doi: 10.1111/tra.12230 25243850

32. Lagace TA, Ridgway ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochim Biophys Acta BBA—Mol Cell Res. 2013;1833: 2499–2510. doi: 10.1016/j.bbamcr.2013.05.018 23711956

33. Yamashita A, Hayashi Y, Nemoto-Sasaki Y, Ito M, Oka S, Tanikawa T, et al. Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms. Prog Lipid Res. 2014;53: 18–81. doi: 10.1016/j.plipres.2013.10.001 24125941

34. Mackenzie JM, Khromykh AA, Parton RG. Cholesterol Manipulation by West Nile Virus Perturbs the Cellular Immune Response. Cell Host Microbe. 2007;2: 229–239. doi: 10.1016/j.chom.2007.09.003 18005741

35. Yamashita A, Hayashi Y, Matsumoto N, Nemoto-Sasaki Y, Oka S, Tanikawa T, et al. Glycerophosphate/Acylglycerophosphate Acyltransferases. Biology. 2014;3: 801–830. doi: 10.3390/biology3040801 25415055

36. Dircks LK, Ke J, Sul HS. A Conserved Seven Amino Acid Stretch Important for Murine Mitochondrial Glycerol-3-phosphate Acyltransferase Activity. J Biol Chem. 1999;274: 34728–34734. doi: 10.1074/jbc.274.49.34728 10574940

37. Lu B, Jiang YJ, Zhou Y, Xu FY, Hatch GM, Choy PC. Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart. Biochem J. 2005;385: 469–477. doi: 10.1042/BJ20041348 15367102

38. Yamashita A, Nakanishi H, Suzuki H, Kamata R, Tanaka K, Waku K, et al. Topology of acyltransferase motifs and substrate specificity and accessibility in 1-acyl-sn-glycero-3-phosphate acyltransferase 1. Biochim Biophys Acta BBA—Mol Cell Biol Lipids. 2007;1771: 1202–1215. doi: 10.1016/j.bbalip.2007.07.002 17707131

39. Colpitts TM, Cox J, Vanlandingham DL, Feitosa FM, Cheng G, Kurscheid S, et al. Alterations in the Aedes aegypti Transcriptome during Infection with West Nile, Dengue and Yellow Fever Viruses. Rice CM, editor. PLoS Pathog. 2011;7: e1002189. doi: 10.1371/journal.ppat.1002189 21909258

40. Gale SE, Frolov A, Han X, Bickel PE, Cao L, Bowcock A, et al. A Regulatory Role for 1-Acylglycerol-3-phosphate-O-acyltransferase 2 in Adipocyte Differentiation. J Biol Chem. 2006;281: 11082–11089. doi: 10.1074/jbc.M509612200 16495223

41. Merrill AH. Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics. Chem Rev. 2011;111: 6387–6422. doi: 10.1021/cr2002917 21942574

42. Lipton BA, Davidson EP, Ginsberg BH, Yorek MA. Ethanolamine metabolism in cultured bovine aortic endothelial cells. J Biol Chem. 1990;265: 7195–7201. 2110161

43. Liebscher S, Ambrose RL, Aktepe TE, Mikulasova A, Prier JE, Gillespie LK, et al. Phospholipase A2 activity during the replication cycle of the flavivirus West Nile virus. PLoS Pathog. 2018;14. doi: 10.1371/journal.ppat.1007029 29709018

44. Hollenback D, Bonham L, Law L, Rossnagle E, Romero L, Carew H, et al. Substrate specificity of lysophosphatidic acid acyltransferase β—evidence from membrane and whole cell assays. J Lipid Res. 2006;47: 593–604. doi: 10.1194/jlr.M500435-JLR200 16369050

45. Prasad SS, Garg A, Agarwal AK. Enzymatic activities of the human AGPAT isoform 3 and isoform 5: localization of AGPAT5 to mitochondria. J Lipid Res. 2011;52: 451–462. doi: 10.1194/jlr.M007575 21173190

46. Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res. 2004;43: 134–176. doi: 10.1016/s0163-7827(03)00051-1 14654091

47. Ashour J, Laurent-Rolle M, Shi P-Y, García-Sastre A. NS5 of Dengue Virus Mediates STAT2 Binding and Degradation. J Virol. 2009;83: 5408–5418. doi: 10.1128/JVI.02188-08 19279106

48. Merino-Ramos T, Jiménez de Oya N, Saiz J-C, Martín-Acebes MA. Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-O-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus. Antimicrob Agents Chemother. 2017;61. doi: 10.1128/AAC.00376-17 28507114

49. Miller S, Kastner S, Krijnse-Locker J, Bühler S, Bartenschlager R. The Non-structural Protein 4A of Dengue Virus Is an Integral Membrane Protein Inducing Membrane Alterations in a 2K-regulated Manner. J Biol Chem. 2007;282: 8873–8882. doi: 10.1074/jbc.M609919200 17276984

50. Fajardo-Sánchez E, Galiano V, Villalaín J. Spontaneous membrane insertion of a dengue virus NS2A peptide. Arch Biochem Biophys. 2017;627: 56–66. doi: 10.1016/j.abb.2017.06.016 28666739

51. Caviglia JM, Dumm INT de G, Coleman RA, Igal RA. Phosphatidylcholine deficiency upregulates enzymes of triacylglycerol metabolism in CHO cells. J Lipid Res. 2004;45: 1500–1509. doi: 10.1194/jlr.M400079-JLR200 15175356

52. Meer G van, Kroon AIPM de. Lipid map of the mammalian cell. J Cell Sci. 2011;124: 5–8. doi: 10.1242/jcs.071233 21172818

53. Richard AS, Zhang A, Park S-J, Farzan M, Zong M, Choe H. Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses. Proc Natl Acad Sci U S A. 2015;112: 14682–14687. doi: 10.1073/pnas.1508095112 26575624

54. Carnec X, Meertens L, Dejarnac O, Perera-Lecoin M, Hafirassou ML, Kitaura J, et al. The Phosphatidylserine and Phosphatidylethanolamine Receptor CD300a Binds Dengue Virus and Enhances Infection. J Virol. 2016;90: 92–102. doi: 10.1128/JVI.01849-15 26468529

55. Xu K, Nagy PD. RNA virus replication depends on enrichment of phosphatidylethanolamine at replication sites in subcellular membranes. Proc Natl Acad Sci U S A. 2015;112: E1782–E1791. doi: 10.1073/pnas.1418971112 25810252

56. Belov G. Less Grease, Please. Phosphatidylethanolamine Is the Only Lipid Required for Replication of a (+)RNA Virus. Viruses. 2015;7: 3500–3505. doi: 10.3390/v7072784 26131959

57. Sim S, Jupatanakul N, Dimopoulos G. Mosquito Immunity against Arboviruses. Viruses. 2014;6: 4479–4504. doi: 10.3390/v6114479 25415198

58. West J, Tompkins CK, Balantac N, Nudelman E, Meengs B, White T, et al. Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells. DNA Cell Biol. 1997;16: 691–701. doi: 10.1089/dna.1997.16.691 9212163

59. Kanthong N, Laosutthipong C, Flegel TW. Response to Dengue virus infections altered by cytokine-like substances from mosquito cell cultures. BMC Microbiol. 2010;10: 290. doi: 10.1186/1471-2180-10-290 21078201

60. Barletta ABF, Silva MCLN, Sorgine MHF. Validation of Aedes aegypti Aag-2 cells as a model for insect immune studies. Parasit Vectors. 2012;5: 148. doi: 10.1186/1756-3305-5-148 22827926

61. Schreiber MJ, Holmes EC, Ong SH, Soh HSH, Liu W, Tanner L, et al. Genomic Epidemiology of a Dengue Virus Epidemic in Urban Singapore. J Virol. 2009;83: 4163–4173. doi: 10.1128/JVI.02445-08 19211734

62. Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, et al. MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015;12: 523–526. doi: 10.1038/nmeth.3393 25938372

63. Tsugawa H, Kind T, Nakabayashi R, Yukihira D, Tanaka W, Cajka T, et al. Hydrogen Rearrangement Rules: Computational MS/MS Fragmentation and Structure Elucidation Using MS-FINDER Software. Anal Chem. 2016;88: 7946–7958. doi: 10.1021/acs.analchem.6b00770 27419259

64. Sumner LW, Amberg A, Barrett D, Beale MH, Beger R, Daykin CA, et al. Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics Off J Metabolomic Soc. 2007;3: 211–221. doi: 10.1007/s11306-007-0082-2 24039616

65. Tsugawa H, Nakabayashi R, Mori T, Yamada Y, Takahashi M, Rai A, et al. A cheminformatics approach to characterize metabolomes in stable-isotope-labeled organisms. Nat Methods. 2019;16: 295. doi: 10.1038/s41592-019-0358-2 30923379

66. Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018;46: W486–W494. doi: 10.1093/nar/gky310 29762782

67. Fraiture M, Baxter RHG, Steinert S, Chelliah Y, Frolet C, Quispe-Tintaya W, et al. Two Mosquito LRR Proteins Function as Complement Control Factors in the TEP1-Mediated Killing of Plasmodium. Cell Host Microbe. 2009;5: 273–284. doi: 10.1016/j.chom.2009.01.005 19286136

68. Johnson BW, Russell BJ, Lanciotti RS. Serotype-Specific Detection of Dengue Viruses in a Fourplex Real-Time Reverse Transcriptase PCR Assay. J Clin Microbiol. 2005;43: 4977–4983. doi: 10.1128/JCM.43.10.4977-4983.2005 16207951

69. Manokaran G, Finol E, Wang C, Gunaratne J, Bahl J, Ong EZ, et al. Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness. Science. 2015;350: 217. doi: 10.1126/science.aab3369 26138103