Systemic Expression of Kaposi Sarcoma Herpesvirus (KSHV) Vflip in Endothelial Cells Leads to a Profound Proinflammatory Phenotype and Myeloid Lineage Remodeling

English version České info

Kaposi’s sarcoma (KS) is the most common cancer in men infected with HIV, and also among the most frequent malignancies in Sub-Equatorial Africa. KS is a tumor of endothelial cell origin that is caused by infection with a gamma-herpesvirus, called KS herpesvirus (KSHV) or human herpesvirus 8 (HHV-8). KSHV vFLIP is a viral oncoprotein expressed during latent infection. We report here the generation and characterization of mice expressing KSHV vFLIP in an inducible manner in endothelial cells. Transgenic mice showed: 1) systemic endothelial abnormalities, with the presence of fusiform cells reminiscent of the spindle cells found in KS, 2) development of a profound perturbation in serum cytokines, reminiscent of the cytokine storm characteristic of KSHV-associated cytokine syndrome (KICS), and 3) remodeling of myeloid differentiation with expansion of myeloid cells displaying a suppressive immunophenotype that potentially favors host immune evasion, angiogenesis and tumor progression. This is the first example of significant changes in myeloid differentiation, vascular abnormalities and cytokine perturbation entirely initiated by ectopic expression of a single viral gene, making this mouse model a useful system to dissect the mechanisms viruses use to manipulate the host microenvironment culminating in sabotage of immunity and development of vascular lesions.

Vyšlo v časopise: Systemic Expression of Kaposi Sarcoma Herpesvirus (KSHV) Vflip in Endothelial Cells Leads to a Profound Proinflammatory Phenotype and Myeloid Lineage Remodeling. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004581
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004581

Souhrn

Zdroje

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266: 1865–1869. 7997879

2. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. 7700311

3. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, et al. (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86: 1276–1280. 7632932

4. Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, et al. (2010) An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis 51: 350–358. doi: 10.1086/654798 20583924

5. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R (2012) Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome. Front Microbiol 3: 73. doi: 10.3389/fmicb.2012.00073 22403576

6. Li CF, Ye H, Liu H, Du MQ, Chuang SS (2006) Fatal HHV-8-associated hemophagocytic syndrome in an HIV-negative immunocompetent patient with plasmablastic variant of multicentric Castleman disease (plasmablastic microlymphoma). Am J Surg Pathol 30: 123–127. 16330952

7. Dispenzieri A (2007) POEMS syndrome. Blood Rev 21: 285–299. 17850941

8. Cesarman E, Mesri EA, Gershengorn MC (2000) Viral G protein-coupled receptor and Kaposi’s sarcoma: a model of paracrine neoplasia? J Exp Med 191: 417–422. 10662787

9. Ganem D (2010) KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest 120: 939–949. doi: 10.1172/JCI40567 20364091

10. Mesri EA, Cesarman E, Boshoff C (2010) Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719. doi: 10.1038/nrc2888 20865011

11. Chang HH, Ganem D (2013) A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 13: 429–440. doi: 10.1016/j.chom.2013.03.009 23601105

12. Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS (1998) Transcription mapping of the Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J Virol 72: 1005–1012. 9444993

13. Chaudhary PM, Jasmin A, Eby MT, Hood L (1999) Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18: 5738–5746. 10523854

14. Field N, Low W, Daniels M, Howell S, Daviet L, et al. (2003) KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci 116: 3721–3728. 12890756

15. Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, et al. (2006) NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 107: 3295–3302. doi: 10.1182/blood-2005-07-2730 16380446

16. Keller SA, Schattner EJ, Cesarman E (2000) Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96: 2537–2542. 11001908

17. Guasparri I, Keller SA, Cesarman E (2004) KSHV vFLIP Is Essential for the Survival of Infected Lymphoma Cells. J Exp Med 199: 993–1003. doi: 10.1084/jem.20031467 15067035

18. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, et al. (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388: 190–195. 9217161

19. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, et al. (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386: 517–521. 9087414

20. Krueger A, Baumann S, Krammer PH, Kirchhoff S (2001) FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 21: 8247–8254. doi: 10.1128/MCB.21.24.8247-8254.2001 11713262

21. Matta H, Chaudhary PM (2004) Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci U S A 101: 9399–9404. doi: 10.1073/pnas.0308016101 15190178

22. Lee JS, Li Q, Lee JY, Lee SH, Jeong JH, et al. (2009) FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol 11: 1355–1362. doi: 10.1038/ncb1980 19838173

23. Ballon G, Chen K, Perez R, Tam W, Cesarman E (2011) Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 121: 1141–1153. doi: 10.1172/JCI44417 21339646

24. Sin SH, Dittmer DP (2013) Viral latency locus augments B-cell response in vivo to induce chronic marginal zone enlargement, plasma cell hyperplasia, and lymphoma. Blood 121: 2952–2963. doi: 10.1182/blood-2012-03-415620 23365457

25. Chugh P, Matta H, Schamus S, Zachariah S, Kumar A, et al. (2005) Constitutive NF-kappaB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice. Proc Natl Acad Sci U S A 102: 12885–12890. doi: 10.1073/pnas.0408577102 16120683

26. Hussein MR (2008) Immunohistological evaluation of immune cell infiltrate in cutaneous Kaposi’s sarcoma. Cell Biol Int 32: 157–162. 17950633

27. Grossmann C, Podgrabinska S, Skobe M, Ganem D (2006) Activation of NF-kappaB by the latent vFLIP gene of Kaposi’s sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype. J Virol 80: 7179–7185. doi: 10.1128/JVI.01603-05 16809323

28. Sakakibara S, Pise-Masison CA, Brady JN, Tosato G (2009) Gene regulation and functional alterations induced by Kaposi’s sarcoma-associated herpesvirus-encoded ORFK13/vFLIP in endothelial cells. J Virol 83: 2140–2153. doi: 10.1128/JVI.01871-08 19091861

29. Alkharsah KR, Singh VV, Bosco R, Santag S, Grundhoff A, et al. (2011) Deletion of Kaposi’s sarcoma-associated herpesvirus FLICE inhibitory protein, vFLIP, from the viral genome compromises the activation of STAT1-responsive cellular genes and spindle cell formation in endothelial cells. J Virol 85: 10375–10388. doi: 10.1128/JVI.00226-11 21795355

30. Douglas JL, Gustin JK, Dezube B, Pantanowitz JL, Moses AV (2007) Kaposi’s sarcoma: a model of both malignancy and chronic inflammation. Panminerva Med 49: 119–138. 17912148

31. Regezi JA, MacPhail LA, Daniels TE, DeSouza YG, Greenspan JS, et al. (1993) Human immunodeficiency virus-associated oral Kaposi’s sarcoma. A heterogeneous cell population dominated by spindle-shaped endothelial cells. Am J Pathol 143: 240–249. 8100400

32. Dupin N, Fisher C, Kellam P, Ariad S, Tulliez M, et al. (1999) Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A 96: 4546–4551. 10200299

33. Weninger W, Partanen TA, Breiteneder-Geleff S, Mayer C, Kowalski H, et al. (1999) Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells. Lab Invest 79: 243–251. 10068212

34. Kahn HJ, Bailey D, Marks A (2002) Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol 15: 434–440. 11950918

35. Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, et al. (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36: 687–693. 15220918

36. Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, et al. (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36: 683–685. 15220917

37. Carroll PA, Brazeau E, Lagunoff M (2004) Kaposi’s sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology 328: 7–18. doi: 10.1016/j.virol.2004.07.008 15380353

38. Alva JA, Zovein AC, Monvoisin A, Murphy T, Salazar A, et al. (2006) VE-Cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells. Dev Dyn 235: 759–767. 16450386

39. Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, et al. (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465: 483–486. doi: 10.1038/nature09002 20445537

40. Punj V, Matta H, Schamus S, Chaudhary PM (2009) Integrated microarray and multiplex cytokine analyses of Kaposi’s Sarcoma Associated Herpesvirus viral FLICE Inhibitory Protein K13 affected genes and cytokines in human blood vascular endothelial cells. BMC Med Genomics 2: 50. doi: 10.1186/1755-8794-2-50 19660139

41. Apolloni E, Bronte V, Mazzoni A, Serafini P, Cabrelle A, et al. (2000) Immortalized myeloid suppressor cells trigger apoptosis in antigen-activated T lymphocytes. J Immunol 165: 6723–6730. 11120790

42. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, et al. (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450: 825–831. 18064003

43. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12: 253–268. doi: 10.1038/nri3175 22437938

44. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, et al. (2010) Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A 107: 21248–21255. doi: 10.1073/pnas.1015855107 21081700

45. Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, et al. (2001) Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood 97: 3244–3250. 11342455

46. Ballard DW, Bohnlein E, Lowenthal JW, Wano Y, Franza BR, et al. (1988) HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science 241: 1652–1655. 2843985

47. Santee SM, Owen-Schaub LB (1996) Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization. J Biol Chem 271: 21151–21159. 8702885

48. Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, et al. (2003) Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi’s sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3: 23–36. 12559173

49. Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, et al. (2007) In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi’s sarcoma. Cancer Cell 11: 245–258. doi: 10.1016/j.ccr.2007.01.015 17349582

50. Staszel T, Zapala B, Polus A, Sadakierska-Chudy A, Kiec-Wilk B, et al. (2011) Role of microRNAs in endothelial cell pathophysiology. Pol Arch Med Wewn 121: 361–366. 21946298

51. Zhu Y, Haecker I, Yang Y, Gao SJ, Renne R (2013) gamma-Herpesvirus-encoded miRNAs and their roles in viral biology and pathogenesis. Curr Opin Virol 3: 266–275. doi: 10.1016/j.coviro.2013.05.013 23743127

52. Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, et al. (1999) Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93: 4034–4043. 10361100

53. Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, et al. (2006) The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10: 133–143. 16904612

54. Verschuren EW, Klefstrom J, Evan GI, Jones N (2002) The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2: 229–241. 12242155

55. Sugaya M, Watanabe T, Yang A, Starost MF, Kobayashi H, et al. (2005) Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter. Blood 105: 2356–2363. 15536152

56. Yang TY, Chen SC, Leach MW, Manfra D, Homey B, et al. (2000) Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med 191: 445–454. 10662790

57. Jones T, Ye F, Bedolla R, Huang Y, Meng J, et al. (2012) Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV. J Clin Invest 122: 1076–1081. doi: 10.1172/JCI58530 22293176

58. Wang LX, Kang G, Kumar P, Lu W, Li Y, et al. (2014) Humanized-BLT mouse model of Kaposi’s sarcoma-associated herpesvirus infection. Proc Natl Acad Sci U S A 111: 3146–3151. doi: 10.1073/pnas.1318175111 24516154

59. Soubrier M, Dubost JJ, Serre AF, Ristori JM, Sauvezie B, et al. (1997) Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum 40: 786–787. 9125266

60. Burger R, Neipel F, Fleckenstein B, Savino R, Ciliberto G, et al. (1998) Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells. Blood 91: 1858–1863. 9490667

61. Hudnall SD, Chen T, Brown K, Angel T, Schwartz MR, et al. (2003) Human herpesvirus-8-positive microvenular hemangioma in POEMS syndrome. Arch Pathol Lab Med 127: 1034–1036. 12873182

62. Belec L, Mohamed AS, Authier FJ, Hallouin MC, Soe AM, et al. (1999) Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman’s disease. Blood 93: 3643–3653. 10339470

63. Belec L, Authier FJ, Mohamed AS, Soubrier M, Gherardi RK (1999) Antibodies to human herpesvirus 8 in POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome with multicentric Castleman’s disease. Clin Infect Dis 28: 678–679. 10194095

64. Kim DE, Kim HJ, Kim YA, Lee KW (2000) Kaposi’s sarcoma herpesvirus-associated Castleman’s disease with POEMS syndrome. Muscle Nerve 23: 436–439. 10679723

65. Papo T, Soubrier M, Marcelin AG, Calvez V, Wechsler B, et al. (1999) Human herpesvirus 8 infection, Castleman’s disease and POEMS syndrome. Br J Haematol 104: 932–933. 10192466

66. Zumo L, Grewal RP (2002) Castleman’s disease-associated neuropathy: no evidence of human herpesvirus type 8 infection. J Neurol Sci 195: 47–50. 11867073

67. Fainaru O, Hantisteanu S, Hallak M (2011) Immature myeloid cells accumulate in mouse placenta and promote angiogenesis. Am J Obstet Gynecol 204: 544 e518–523. doi: 10.1016/j.ajog.2011.01.060 21420066

68. Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32: 19–25. doi: 10.1016/j.it.2010.10.002 21067974

69. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182: 4499–4506. doi: 10.4049/jimmunol.0802740 19342621

70. Qin Z, Kearney P, Plaisance K, Parsons CH (2010) Pivotal advance: Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes. J Leukoc Biol 87: 25–34. doi: 10.1189/jlb.0409251 20052801

71. Cirone M, Lucania G, Aleandri S, Borgia G, Trivedi P, et al. (2008) Suppression of dendritic cell differentiation through cytokines released by Primary Effusion Lymphoma cells. Immunol Lett 120: 37–41. doi: 10.1016/j.imlet.2008.06.011 18680763

72. Drexler HG, Meyer C, Gaidano G, Carbone A (1999) Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines. Leukemia 13: 634–640. 10214873

73. Jones KD, Aoki Y, Chang Y, Moore PS, Yarchoan R, et al. (1999) Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi’s sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood 94: 2871–2879. 10515891

74. Della Bella S, Nicola S, Brambilla L, Riva A, Ferrucci S, et al. (2006) Quantitative and functional defects of dendritic cells in classic Kaposi’s sarcoma. Clin Immunol 119: 317–329. 16527545

75. Lambert M, Gannage M, Karras A, Abel M, Legendre C, et al. (2006) Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma. Blood 108: 3871–3880. 16926293

76. Parravicini C, Chandran B, Corbellino M, Berti E, Paulli M, et al. (2000) Differential viral protein expression in Kaposi’s sarcoma-associated herpesvirus-infected diseases: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Am J Pathol 156: 743–749. doi: 10.1016/S0002-9440(10)64940-1 10702388