Identification of new antiviral agents against Kaposi’s sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation


Autoři: Jungang Chen aff001;  Lu Dai aff001;  Alana Goldstein aff002;  Haiwei Zhang aff003;  Wei Tang aff003;  J. Craig Forrest aff004;  Steven R. Post aff001;  Xulin Chen aff003;  Zhiqiang Qin aff001
Působiště autorů: Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America aff001;  Departments of Diagnostic Sciences, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America aff002;  State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei, China aff003;  Department of Microbiology & Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America aff004
Vyšlo v časopise: Identification of new antiviral agents against Kaposi’s sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation. PLoS Pathog 15(12): e1008156. doi:10.1371/journal.ppat.1008156
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008156

Souhrn

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human cancers, such as Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL). Current treatment options for KSHV infection and virus associated diseases are sometimes ineffective, therefore, more effectively antiviral agents are urgently needed. As a herpesvirus, lytic replication is critical for KSHV pathogenesis and oncogenesis. In this study, we have established a high-throughput screening assay by using an inducible KSHV+ cell-line, iSLK.219. After screening a compound library that consisted of 1280 Food and Drug Administration (FDA)-approved drugs, 15 hit compounds that effectively inhibited KSHV virion production were identified, most of which have never been reported with anti-KSHV activities. Interestingly, 3 of these drugs target histamine receptors or signaling. Our data further confirmed that antagonists targeting different histamine receptors (HxRs) displayed excellent inhibitory effects on KSHV lytic replication from induced iSLK.219 or BCBL-1 cells. In contrast, histamine and specific agonists of HxRs promoted viral lytic replication from induced iSLK.219 or KSHV-infected primary cells. Mechanistic studies indicated that downstream MAPK and PI3K/Akt signaling pathways were required for histamine/receptors mediated promotion of KSHV lytic replication. Direct knockdown of HxRs in iSLK.219 cells effectively blocked viral lytic gene expression during induction. Using samples from a cohort of HIV+ patients, we found that the KSHV+ group has much higher levels of histamine in their plasma and saliva than the KSHV- group. Taken together, our data have identified new anti-KSHV agents and provided novel insights into the molecular bases of host factors that contribute to lytic replication and reactivation of this oncogenic herpesvirus.

Klíčová slova:

Drug screening – Histamine – Kaposi's sarcoma-associated herpesvirus – Library screening – MAPK signaling cascades – Saliva – Viral replication – Virions


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. doi: 10.1126/science.7997879 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. doi: 10.1056/NEJM199505043321802 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. Qin J, Lu C (2017) Infection of KSHV and Interaction with HIV: The Bad Romance. Adv Exp Med Biol 1018: 237–251. doi: 10.1007/978-981-10-5765-6_15 29052142

5. Chen Y-B, Rahemtullah A, Hochberg E (2007) Primary Effusion Lymphoma. The Oncologist 12: 569–576. doi: 10.1634/theoncologist.12-5-569 17522245

6. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R (2017) Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome (vol 3, pg 73, 2012). Frontiers in Microbiology 8.

7. Dittmer DP, Damania B (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126: 3165–3175. doi: 10.1172/JCI84418 27584730

8. Coen N, Duraffour S, Snoeck R, Andrei G (2014) KSHV targeted therapy: an update on inhibitors of viral lytic replication. Viruses 6: 4731–4759. doi: 10.3390/v6114731 25421895

9. Greene W, Kuhne K, Ye F, Chen J, Zhou F, et al. (2007) Molecular biology of KSHV in relation to AIDS-associated oncogenesis. Cancer Treat Res 133: 69–127. doi: 10.1007/978-0-387-46816-7_3 17672038

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. Renne R, Lagunoff M, Zhong W, Ganem D (1996) The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 70: 8151–8154. 8892944

12. Uppal T, Banerjee S, Sun ZG, Verma SC, Robertson ES (2014) KSHV LANA-The Master Regulator of KSHV Latency. Viruses-Basel 6: 4961–4998.

13. Ye F, Lei X, Gao SJ (2011) Mechanisms of Kaposi's Sarcoma-Associated Herpesvirus Latency and Reactivation. Adv Virol 2011.

14. Lu M, Suen J, Frias C, Pfeiffer R, Tsai MH, et al. (2004) Dissection of the Kaposi's sarcoma-associated herpesvirus gene expression program by using the viral DNA replication inhibitor cidofovir. Journal of Virology 78: 13637–13652. doi: 10.1128/JVI.78.24.13637-13652.2004 15564474

15. Blasig C, Zietz C, Haar B, Neipel F, Esser S, et al. (1997) Monocytes in Kaposi's sarcoma lesions are productively infected by human herpesvirus 8. J Virol 71: 7963–7968. 9311888

16. Aneja KK, Yuan Y (2017) Reactivation and Lytic Replication of Kaposi’s Sarcoma-Associated Herpesvirus: An Update. Frontiers in Microbiology 8.

17. Cavallin LE, Goldschmidt-Clermont P, Mesri EA (2014) Molecular and cellular mechanisms of KSHV oncogenesis of Kaposi's sarcoma associated with HIV/AIDS. PLoS Pathog 10: e1004154. doi: 10.1371/journal.ppat.1004154 25010730

18. Liang C, Lee JS, Jung JU (2008) Immune evasion in Kaposi's sarcoma-associated herpes virus associated oncogenesis. Semin Cancer Biol 18: 423–436. doi: 10.1016/j.semcancer.2008.09.003 18948197

19. Manners O, Murphy JC, Coleman A, Hughes DJ, Whitehouse A (2018) Contribution of the KSHV and EBV lytic cycles to tumourigenesis. Curr Opin Virol 32: 60–70. doi: 10.1016/j.coviro.2018.08.014 30268927

20. Gantt S, Casper C (2011) Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. Curr Opin Infect Dis 24: 295–301. doi: 10.1097/QCO.0b013e3283486d04 21666458

21. Schwartz RA (2004) Kaposi's sarcoma: an update. J Surg Oncol 87: 146–151. doi: 10.1002/jso.20090 15334644

22. Casper C, Nichols WG, Huang ML, Corey L, Wald A (2004) Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 103: 1632–1634. doi: 10.1182/blood-2003-05-1721 14615380

23. Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, et al. (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34: 33–58. doi: 10.1016/j.tips.2012.11.001 23254267

24. Movat HZ (1987) The role of histamine and other mediators in microvascular changes in acute inflammation. Can J Physiol Pharmacol 65: 451–457. doi: 10.1139/y87-077 3555750

25. Xie H, He SH (2005) Roles of histamine and its receptors in allergic and inflammatory bowel diseases. World J Gastroenterol 11: 2851–2857. doi: 10.3748/wjg.v11.i19.2851 15902718

26. Dong H, Zhang W, Zeng X, Hu G, Zhang H, et al. (2014) Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Mol Neurobiol 49: 1487–1500. doi: 10.1007/s12035-014-8697-6 24752587

27. Bakker RA, Schoonus SB, Smit MJ, Timmerman H, Leurs R (2001) Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol 60: 1133–1142. doi: 10.1124/mol.60.5.1133 11641442

28. Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, et al. (2016) Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation. Aging 8: 3065–3090. doi: 10.18632/aging.101113 27875806

29. Faustino-Rocha AI, Ferreira R, Gama A, Oliveira PA, Ginja M (2017) Antihistamines as promising drugs in cancer therapy. Life Sciences 172: 27–41. doi: 10.1016/j.lfs.2016.12.008 27986539

30. Ayers LW, Barbachano-Guerrero A, McAllister SC, Ritchie JA, Asiago-Reddy E, et al. (2018) Mast Cell Activation and KSHV Infection in Kaposi Sarcoma. Clin Cancer Res 24: 5085–5097. doi: 10.1158/1078-0432.CCR-18-0873 30084838

31. Chen J, Jiang L, Lan K, Chen X (2015) Celecoxib Inhibits the Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus through Down-Regulation of RTA Expression by Inhibiting the Activation of p38 MAPK. Viruses 7: 2268–2287. doi: 10.3390/v7052268 25951487

32. Myoung J, Ganem D (2011) Generation of a doxycycline-inducible KSHV producer cell line of endothelial origin: Maintenance of tight latency with efficient reactivation upon induction. Journal of Virological Methods 174: 12–21. doi: 10.1016/j.jviromet.2011.03.012 21419799

33. Mettenleiter TC (2002) Herpesvirus assembly and egress. J Virol 76: 1537–1547. doi: 10.1128/JVI.76.4.1537-1547.2002 11799148

34. Rordam OM, Lenouvel EW, Maalo M (2012) Successful treatment of extensive vitiligo with monobenzone. J Clin Aesthet Dermatol 5: 36–39.

35. Jansen PM, Danser AH, Imholz BP, van den Meiracker AH (2009) Aldosterone-receptor antagonism in hypertension. J Hypertens 27: 680–691. doi: 10.1097/HJH.0b013e32832810ed 19516169

36. Verma D, Thompson J, Swaminathan S (2016) Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proceedings of the National Academy of Sciences of the United States of America 113: 3609–3614. doi: 10.1073/pnas.1523686113 26976570

37. Thieulent CJ, Hue ES, Fortier CI, Dallemagne P, Zientara S, et al. (2019) Screening and evaluation of antiviral compounds against Equid alpha-herpesviruses using an impedance-based cellular assay. Virology 526: 105–116. doi: 10.1016/j.virol.2018.10.013 30388626

38. Bases RE, Mendez F (1997) Topoisomerase inhibition by lucanthone, an adjuvant in radiation therapy. Int J Radiat Oncol Biol Phys 37: 1133–1137. doi: 10.1016/s0360-3016(97)00113-2 9169823

39. Gonzalez-Molleda L, Wang Y, Yuan Y (2012) Potent antiviral activity of topoisomerase I and II inhibitors against Kaposi's sarcoma-associated herpesvirus. Antimicrob Agents Chemother 56: 893–902. doi: 10.1128/AAC.05274-11 22106228

40. Alcindor T, Beauger N (2011) Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol 18: 18–25. doi: 10.3747/co.v18i1.708 21331278

41. A. Spasov A, Iezhitsa I, Bugaeva L, A. Anisimova V (1999) Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties (a review). 232–243 p.

42. Lee S, Deng H, Yu F, Melega WP, Damoiseaux R, et al. (2008) Regulation of Kaposi's sarcoma-associated herpesvirus reactivation by dopamine receptor-mediated signaling pathways. J Acquir Immune Defic Syndr 48: 531–540. doi: 10.1097/QAI.0b013e31817fbdcf 18645521

43. Chang M, Brown HJ, Collado-Hidalgo A, Arevalo JM, Galic Z, et al. (2005) beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. Journal of Virology 79: 13538–13547. doi: 10.1128/JVI.79.21.13538-13547.2005 16227274

44. Shi Z, Fultz RS, Engevik MA, Gao C, Hall A, et al. (2019) Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis. Am J Physiol Gastrointest Liver Physiol 316: G205–G216. doi: 10.1152/ajpgi.00212.2018 30462522

45. Rapanelli M, Frick LR, Horn KD, Schwarcz RC, Pogorelov V, et al. (2016) The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem 291: 21042–21052. doi: 10.1074/jbc.M116.731406 27510032

46. Pan H, Xie J, Ye F, Gao SJ (2006) Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol 80: 5371–5382. doi: 10.1128/JVI.02299-05 16699017

47. Liu X, Cohen JI (2015) The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside. Virology 479–480: 568–577. doi: 10.1016/j.virol.2015.02.040 25798530

48. Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H (1991) Biochemical markers of anaphylactoid reactions to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 75: 945–949. doi: 10.1097/00000542-199112000-00004 1741515

49. Tabarean IV (2016) Histamine receptor signaling in energy homeostasis. Neuropharmacology 106: 13–19. doi: 10.1016/j.neuropharm.2015.04.011 26107117

50. Massari NA, Nicoud MB, Medina VA (2018) Histamine receptors and cancer pharmacology: an update. Br J Pharmacol.

51. Stürzl M, Gaus D, Dirks WG, Ganem D, Jochmann R (2013) Kaposi's sarcoma-derived cell line SLK is not of endothelial origin, but is a contaminant from a known renal carcinoma cell line. International Journal of Cancer 132: 1954–1958. doi: 10.1002/ijc.27849 22987579

52. Vieira J, O'Hearn PM (2004) Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression. Virology 325: 225–240. doi: 10.1016/j.virol.2004.03.049 15246263

53. An LW, Liu R, Tang W, Wu JG, Chen XL (2014) Screening and identification of inhibitors against influenza A virus from a US drug collection of 1280 drugs. Antiviral Research 109: 54–63. doi: 10.1016/j.antiviral.2014.06.007 24971493

54. Dai L, Del Valle L, Miley W, Whitby D, Ochoa AC, et al. (2018) Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development. Oncogene.

55. Mbisa GL, Miley W, Gamache CJ, Gillette WK, Esposito D, et al. (2010) Detection of antibodies to Kaposi's sarcoma-associated herpesvirus: A new approach using K8.1 ELISA and a newly developed recombinant LANA ELISA. Journal of Immunological Methods 356: 39–46. doi: 10.1016/j.jim.2010.02.015 20211626

56. Benavente Y, Mbisa G, Labo N, Casabonne D, Becker N, et al. (2011) Antibodies against lytic and latent Kaposi's sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study. Br J Cancer 105: 1768–1771. doi: 10.1038/bjc.2011.392 21952625

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Hygiena a epidemiologie Infekční lékařství Laboratoř

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