Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection

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The complement system is an important part of the innate immune system. Pathogens have evolved diverse strategies to evade host immune responses including attack of the complement system. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma (KS), primary effusion lymphoma and a subset of multicentric Castleman's disease. KSHV encodes a number of viral proteins to counter host immune responses during productive lytic replication. On the other hand, KSHV utilizes latency as a default replication program during which it expresses a minimal number of proteins to evade host immune detection. Thus, the complement system is expected to be silent during KSHV latency. In this study, we have found that the complement system is unexpectedly activated in latently KSHV-infected endothelial cells and in KS tumor cells wherein KSHV downregulates the expression of CD55 and CD59 complement regulatory proteins. More interestingly, most of latently KSHV-infected cells not only are resistant to complement-mediated cell killing, but also acquire survival advantage by inducing STAT3 tyrosine phosphorylation. These results demonstrate a novel mechanism by which an oncogenic virus exploits the host innate immune system to promote viral persistent infection.

Vyšlo v časopise: Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection. PLoS Pathog 10(9): e32767. doi:10.1371/journal.ppat.1004412
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004412

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1. CesarmanE, ChangY, MoorePS, SaidJW, KnowlesDM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. New Engl J Med 332: 1186–1191.

2. ChangY, CesarmanE, PessinMS, LeeF, CulpepperJ, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869.

3. SoulierJ, GrolletL, OksenhendlerE, CacoubP, Cazals-HatemD, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280.

4. CesarmanE (2011) Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients. Cancer Lett 305: 163–174.

5. GanemD (2010) KSHV and the pathogenesis of Kaposi's sarcoma: listening to human biology and medicine. J Clin Invest 120: 939–949.

6. YeF, LeiX, GaoSJ (2011) Mechanisms of Kaposi's sarcoma-associated herpesvirus latency and reactivation. Adv Virol 2011: pii: 193860.

7. LeeHR, BruloisK, WongL, JungJU (2012) Modulation of immune system by Kaposi's sarcoma-associated herpesvirus: lessons from viral evasion strategies. Front Microbiol 3: 44.

8. FujimuroM, WuFY, ApRhysC, KajumbulaH, YoungDB, et al. (2003) A novel viral mechanism for dysregulation of beta-catenin in Kaposi's sarcoma-associated herpesvirus latency. Nat Med 9: 300–306.

9. KellerSA, SchattnerEJ, CesarmanE (2000) Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96: 2537–2542.

10. LiuJ, MartinHJ, LiaoG, HaywardSD (2007) The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol 81: 10451–10459.

11. UddinS, HussainAR, Al-HusseinKA, ManogaranPS, WickremaA, et al. (2005) Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 11: 3102–3108.

12. XieJ, AjibadeAO, YeF, KuhneK, GaoSJ (2008) Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways. Virology 371: 139–154.

13. MoodyR, ZhuY, HuangY, CuiX, JonesT, et al. (2013) KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways. PLoS Pathog 9: e1003857.

14. AokiY, FeldmanGM, TosatoG (2003) Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101: 1535–1542.

15. MoldenJ, ChangY, YouY, MoorePS, GoldsmithMA (1997) A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem 272: 19625–19631.

16. PunjabiAS, CarrollPA, ChenL, LagunoffM (2007) Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J Virol 81: 2449–2458.

17. WalportMJ (2001) Complement. Second of two parts. New Engl J Med 344: 1140–1144.

18. WalportMJ (2001) Complement. First of two parts. New Engl J Med 344: 1058–1066.

19. RusH, CudriciC, NiculescuF (2005) The role of the complement system in innate immunity. Immunol Res 33: 103–112.

20. ZipfelPF, SkerkaC (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9: 729–740.

21. TeglaCA, CudriciC, PatelS, TrippeR, RusV, et al. (2011) Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res 51: 45–60.

22. KouserL, Abdul-AzizM, NayakA, StoverCM, SimRB, et al. (2013) Properdin and factor h: opposing players on the alternative complement pathway “see-saw”. Front Immunol 4: 93.

23. MorganHP, SchmidtCQ, GuarientoM, BlaumBS, GillespieD, et al. (2011) Structural basis for engagement by complement factor H of C3b on a self surface. Nat Struct Mol Biol 18: 463–470.

24. PangburnMK, Müller-EberhardHJ (1984) The alternative pathway of complement. Springer Semin Immunol 7: 163–192.

25. RisitanoAM (2013) Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol 734: 155–172.

26. WenzelK, ZabojszczaJ, CarlM, TaubertS, LassA, et al. (2005) Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. J Immunol 175: 6219–6225.

27. Ostrand-RosenbergS (2008) Cancer and complement. Nature Biotechnol 26: 1348–1349.

28. SchraufstatterIU, TrieuK, SikoraL, SriramaraoP, DiScipioR (2002) Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol 169: 2102–2110.

29. RusHG, NiculescuFI, ShinML (2001) Role of the C5b-9 complement complex in cell cycle and apoptosis. Immunol Rev 180: 49–55.

30. FosbrinkM, NiculescuF, RusH (2005) The role of c5b-9 terminal complement complex in activation of the cell cycle and transcription. Immunol Res 31: 37–46.

31. FosbrinkM, NiculescuF, RusV, ShinML, RusH (2006) C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem 281: 19009–19018.

32. HalperinJA, TaratuskaA, Nicholson-WellerA (1993) Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells. J Clin Invest 91: 1974–1978.

33. KunchithapauthamK, RohrerB (2011) Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers. J Biol Chem 286: 23717–23724.

34. RutkowskiMJ, SughrueME, KaneAJ, MillsSA, ParsaAT (2010) Cancer and the complement cascade. Mol Cancer Res: MCR 8: 1453–1465.

35. RicklinD, LambrisJD (2013) Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol 190: 3831–3838.

36. GaoSJ, KingsleyL, HooverDR, SpiraTJ, RinaldoCR, et al. (1996) Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. New Engl J Med 335: 233–241.

37. ZhouF-C, ZhangY-J, DengJ-H, WangX-P, PanH-Y, et al. (2002) Efficient infection by a recombinant Kaposi's sarcoma-associated herpesvirus cloned in a bacterial artificial chromosome: application for genetic analysis. J Virol 76: 6185–6196.

38. LagunoffM, BechtelJ, VenetsanakosE, RoyA-M, AbbeyN, et al. (2002) De novo infection and serial transmission of Kaposi's sarcoma-associated herpesvirus in cultured endothelial cells. J Virol 76: 2440–2448.

39. AnF-Q, FolarinHM, CompitelloN, RothJ, GersonSL, et al. (2006) Long-term-infected telomerase-immortalized endothelial cells: a model for Kaposi's sarcoma-associated herpesvirus latency in vitro and in vivo. J Virol 80: 4833–4846.

40. KochiSK, JohnsonRC (1988) Role of immunoglobulin G in killing of Borrelia burgdorferi by the classical complement pathway. Infect Immun 56: 314–321.

41. Des PrezRM, BryanCS, HawigerJ, ColleyDG (1975) Function of the classical and alternate pathways of human complement in serum treated with ethylene glycol tetraacetic acid and MgCl2-ethylene glycol tetraacetic acid. Infect Immun 11: 1235–1243.

42. SpillerOB, BlackbournDJ, MarkL, ProctorDG, BlomAM (2003) Functional activity of the complement regulator encoded by Kaposi's sarcoma-associated herpesvirus. J Biol Chem 278: 9283–9289.

43. SpillerOB, RobinsonM, O'DonnellE, MilliganS, MorganBP, et al. (2003) Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein. J Virol 77: 592–599.

44. WuJ, WuYQ, RicklinD, JanssenBJ, LambrisJD, et al. (2009) Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol 10: 728–733.

45. PerkinsSJ, NanR, OkemefunaAI, LiK, KhanS, et al. (2010) Multiple interactions of complement Factor H with its ligands in solution: a progress report. Adv Exp Med Biol 703: 25–47.

46. CosynsJP, KazatchkineMD, BhakdiS, MandetC, GrosseteteJ, et al. (1986) Immunohistochemical analysis of C3 cleavage fragments, factor H, and the C5b-9 terminal complex of complement in de novo membranous glomerulonephritis occurring in patients with renal transplant. Clin Nephrol 26: 203–208.

47. LevyDE, DarnellJE (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3: 651–662.

48. KingCA (2013) Kaposi's sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28. J Virol 87: 8779–8791.

49. AlcamiA, KoszinowskiUH (2000) Viral mechanisms of immune evasion. Immunol Today 21: 447–455.

50. CooperPD (1985) Complement and cancer: activation of the alternative pathway as a theoretical base for immunotherapy. Adv Immun Cancer Ther 1: 125–166.

51. KolevM, TownerL, DonevR (2011) Complement in cancer and cancer immunotherapy. Arch Immunol Ther Exp 59: 407–419.

52. SimpsonGR, SchulzTF, WhitbyD, CookPM, BoshoffC, et al. (1996) Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 348: 1133–1138.

53. GuadalupeM, PollockBH, WestbrookS, ReddingS, BullockD, et al. (2011) Risk factors influencing antibody responses to Kaposi's sarcoma-associated herpesvirus latent and lytic antigens in patients under antiretroviral therapy. J AIDS 56: 83–90.

54. ThurmanJM, HolersVM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176: 1305–1310.

55. HainesJL, HauserMA, SchmidtS, ScottWK, OlsonLM, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419–421.

56. EdwardsAO, RitterR3rd, AbelKJ, ManningA, PanhuysenC, et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308: 421–424.

57. HagemanGS, AndersonDH, JohnsonLV, HancoxLS, TaiberAJ, et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102: 7227–7232.

58. KleinRJ, ZeissC, ChewEY, TsaiJY, SacklerRS, et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308: 385–389.

59. CazanderG, JukemaGN, NibberingPH (2012) Complement activation and inhibition in wound healing. Clin Dev Immunol 2012: 534291.

60. FujitaT, HemmiS, KajiwaraM, YabukiM, FukeY, et al. (2012) Complement-mediated chronic inflammation is associated with diabetic microvascular complication. Diabetes Metab Res Rev 29: 220–226.

61. LucasSD, Karlsson-ParraA, NilssonB, GrimeliusL, AkerströmG, et al. (1996) Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Human Pathol 27: 1329–1335.

62. NiculescuF, RusHG, ReteganM, VlaicuR (1992) Persistent complement activation on tumor cells in breast cancer. Am J Pathol 140: 1039–1043.

63. NiehansGA, CherwitzDL, StaleyNA, KnappDJ, DalmassoAP (1996) Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin). Am J Pathol 149: 129–142.

64. CoussensLM, WerbZ (2002) Inflammation and cancer. Nature 420: 860–867.

65. GrivennikovSI, KarinM (2010) Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20: 65–71.

66. DouglasJL, GustinJK, MosesAV, DezubeBJ, PantanowitzL (2010) Kaposi's sarcoma pathogenesis: a triad of viral infection, oncogenesis and chronic inflammation. Transl Biomed 1 (2010)

67. LuttickenC, WegenkaUM, YuanJ, BuschmannJ, SchindlerC, et al. (1994) Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263: 89–92.

68. AkiraS, NishioY, InoueM, WangXJ, WeiS, et al. (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77: 63–71.

69. BenzaquenLR, Nicholson-WellerA, HalperinJA (1994) Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med 179: 985–992.

70. DeoDD, AxelradTW, RobertEG, MarcheselliV, BazanNG, et al. (2002) Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem 277: 21237–21245.

71. SachsenmaierC, SadowskiHB, CooperJA (1999) STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation. Oncogene 18: 3583–3592.

72. WernerS, HofschneiderPH, RothWK (1989) Cells derived from sporadic and AIDS-related Kaposi's sarcoma reveal identical cytochemical and molecular properties in vitro. Int J Cancer 43: 1137–1144.

73. RothWK, WernerS, SchirrenCG, HofschneiderPH (1989) Depletion of PDGF from serum inhibits growth of AIDS-related and sporadic Kaposi's sarcoma cells in culture. Oncogene 4: 483–487.

74. Delli BoviP, CuratolaAM, KernFG, GrecoA, IttmannM, et al. (1987) An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a growth factor that is a member of the FGF family. Cell 50: 729–737.

75. Delli-BoviP, CuratolaAM, NewmanKM, SatoY, MoscatelliD, et al. (1988) Processing, secretion, and biological properties of a novel growth factor of the fibroblast growth factor family with oncogenic potential. Mol Cell Biol 8: 2933–2941.

76. NiculescuF, SoaneL, BadeaT, ShinM, RusH (1999) Tyrosine phosphorylation and activation of Janus kinase 1 and STAT3 by sublytic C5b-9 complement complex in aortic endothelial cells. Immunopharmacology 42: 187–193.

77. YeFC, BlackbournDJ, MengelM, XieJP, QianLW, et al. (2007) Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1. J Virol 81: 3980–3991.

78. YooS-M, ZhouF-C, YeF-C, PanH-Y, GaoS-J (2005) Early and sustained expression of latent and host modulating genes in coordinated transcriptional program of KSHV productive primary infection of human primary endothelial cells. Virology 343: 47–64.