#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice


Human gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), are causatively linked to a spectrum of human oncogenic malignancies. Due to the stringent host restriction, rodents are generally not amenable to infection by EBV and KSHV. Murine gamma herpesvirus 68 (γHV68) is closely related to KSHV and EBV, although infection in mouse does not manifest apparent diseases. Here we developed a recombinant γHV68 that carries the KSHV G protein-coupled receptor, an important signaling molecule implicated in KSHV pathogenesis. Intriguingly, laboratory mice infected with this recombinant γHV68 developed angiogenic lesions that resembled human Kaposi’s sarcoma. This mouse infection with recombinant γHV68 carrying KSHV GPCR represents a useful model to investigate viral oncogenesis induced by human gamma herpesvirus in the context of viral infection.


Vyšlo v časopise: Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1005001
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005001

Souhrn

Human gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), are causatively linked to a spectrum of human oncogenic malignancies. Due to the stringent host restriction, rodents are generally not amenable to infection by EBV and KSHV. Murine gamma herpesvirus 68 (γHV68) is closely related to KSHV and EBV, although infection in mouse does not manifest apparent diseases. Here we developed a recombinant γHV68 that carries the KSHV G protein-coupled receptor, an important signaling molecule implicated in KSHV pathogenesis. Intriguingly, laboratory mice infected with this recombinant γHV68 developed angiogenic lesions that resembled human Kaposi’s sarcoma. This mouse infection with recombinant γHV68 carrying KSHV GPCR represents a useful model to investigate viral oncogenesis induced by human gamma herpesvirus in the context of viral infection.


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. Nador RG, Cesarman E, Knowles DM, Said JW (1995) Herpes-like DNA sequences in a body-cavity-based lymphoma in an HIV-negative patient. N Engl J Med 333: 943.

5. Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, et al. (1997) Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71: 715–719. 8985403

6. Kirshner JR, Staskus K, Haase A, Lagunoff M, Ganem D (1999) Expression of the open reading frame 74 (G-protein-coupled receptor) gene of Kaposi's sarcoma (KS)-associated herpesvirus: implications for KS pathogenesis. J Virol 73: 6006–6014. 10364352

7. Ganem D (2006) KSHV infection and the pathogenesis of Kaposi's sarcoma. Annu Rev Pathol 1: 273–296. 18039116

8. Speck SH, Ganem D (2010) Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe 8: 100–115. doi: 10.1016/j.chom.2010.06.014 20638646

9. Chang H, Wachtman LM, Pearson CB, Lee JS, Lee HR, et al. (2009) Non-human primate model of Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathog 5: e1000606. doi: 10.1371/journal.ppat.1000606 19798430

10. Austgen K, Oakes SA, Ganem D (2012) Multiple defects, including premature apoptosis, prevent Kaposi's sarcoma-associated herpesvirus replication in murine cells. J Virol 86: 1877–1882. doi: 10.1128/JVI.06600-11 22130538

11. Dittmer D, Stoddart C, Renne R, Linquist-Stepps V, Moreno ME, et al. (1999) Experimental transmission of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) to SCID-hu Thy/Liv mice. J Exp Med 190: 1857–1868. 10601360

12. 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

13. Fakhari FD, Jeong JH, Kanan Y, Dittmer DP (2006) The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest 116: 735–742. 16498502

14. 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

15. 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

16. Holst PJ, Rosenkilde MM, Manfra D, Chen SC, Wiekowski MT, et al. (2001) Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J Clin Invest 108: 1789–1796. 11748262

17. Moore PS, Boshoff C, Weiss RA, Chang Y (1996) Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274: 1739–1744. 8939871

18. Virgin HWt, Latreille P, Wamsley P, Hallsworth K, Weck KE, et al. (1997) Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71: 5894–5904. 9223479

19. Doherty PC, Christensen JP, Belz GT, Stevenson PG, Sangster MY (2001) Dissecting the host response to a gamma-herpesvirus. Philos Trans R Soc Lond B Biol Sci 356: 581–593. 11313013

20. Tarakanova VL, Suarez F, Tibbetts SA, Jacoby MA, Weck KE, et al. (2005) Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB beta2 microglobulin-deficient mice. J Virol 79: 14668–14679. 16282467

21. Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7: 79–94. 17251915

22. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E (1997) Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385: 347–350. 9002520

23. Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, et al. (1998) G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391: 86–89. 9422510

24. Geras-Raaka E, Varma A, Ho H, Clark-Lewis I, Gershengorn MC (1998) Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J Exp Med 188: 405–408. 9670053

25. Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I (1998) Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J Clin Invest 102: 1469–1472. 9788958

26. Ho HH, Du D, Gershengorn MC (1999) The N terminus of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity. J Biol Chem 274: 31327–31332. 10531332

27. Lee BJ, Koszinowski UH, Sarawar SR, Adler H (2003) A gammaherpesvirus G protein-coupled receptor homologue is required for increased viral replication in response to chemokines and efficient reactivation from latency. J Immunol 170: 243–251. 12496406

28. Cannon M, Philpott NJ, Cesarman E (2003) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol 77: 57–67. 12477810

29. Martin D, Galisteo R, Ji Y, Montaner S, Gutkind JS (2008) An NF-kappaB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene 27: 1844–1852. 17934524

30. Feng H, Dong X, Negaard A, Feng P (2008) Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity. PLoS Pathog 4: e1000157. doi: 10.1371/journal.ppat.1000157 18802460

31. Zhang J, He S, Wang Y, Brulois K, Lan K, et al. (2015) Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog 11: e1004768. doi: 10.1371/journal.ppat.1004768 25811856

32. 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

33. 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. 17349582

34. Nealy MS, Coleman CB, Li H, Tibbetts SA (2010) Use of a virus-encoded enzymatic marker reveals that a stable fraction of memory B cells express LANA throughout chronic gammaherpesvirus infection. J Virol.

35. Tibbetts SA, Loh J, Van Berkel V, McClellan JS, Jacoby MA, et al. (2003) Establishment and maintenance of gammaherpesvirus latency are independent of infective dose and route of infection. J Virol 77: 7696–7701. 12805472

36. Collins M, Ling V, Carreno BM (2005) The B7 family of immune-regulatory ligands. Genome Biol 6: 223. 15960813

37. Ensoli B, Sirianni MC (1998) Kaposi's sarcoma pathogenesis: a link between immunology and tumor biology. Crit Rev Oncog 9: 107–124. 9973245

38. Dong X, Feng P (2011) Murine gamma herpesvirus 68 hijacks MAVS and IKKbeta to abrogate NFkappaB activation and antiviral cytokine production. PLoS Pathog 7: e1002336. doi: 10.1371/journal.ppat.1002336 22110409

39. Feng H, Sun Z, Farzan MR, Feng P (2010) Sulfotyrosines of the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promote tumorigenesis through autocrine activation. J Virol 84: 3351–3361. doi: 10.1128/JVI.01939-09 20106924

40. Sandford G, Choi YB, Nicholas J (2009) Role of ORF74-encoded viral G protein-coupled receptor in human herpesvirus 8 lytic replication. J Virol 83: 13009–13014. doi: 10.1128/JVI.01399-09 19793819

41. Bottero V, Sharma-Walia N, Kerur N, Paul AG, Sadagopan S, et al. (2009) Kaposi sarcoma-associated herpes virus (KSHV) G protein-coupled receptor (vGPCR) activates the ORF50 lytic switch promoter: a potential positive feedback loop for sustained ORF50 gene expression. Virology 392: 34–51. doi: 10.1016/j.virol.2009.07.002 19640558

42. Tacconi D, Vergori A, Lapini L, Magnolfi A, Carnevali A, et al. (2012) Hepatic Kaposi's sarcoma in a patient affected by AIDS: Correlation between histology and imaging. J Ultrasound 15: 215–219. doi: 10.1016/j.jus.2012.10.004 23730384

43. Sterling RK, Herbener TE, Jacobs GH, Post AB, Carey JT, et al. (1997) Multifocal hepatic lesions in AIDS: an unusual presentation of steatosis. Am J Gastroenterol 92: 1934–1936. 9382073

44. Luburich P, Bru C, Ayuso MC, Azon A, Condom E (1990) Hepatic Kaposi sarcoma in AIDS: US and CT findings. Radiology 175: 172–174. 2179988

45. Micheletti AR, Macedo AC, Silva GB, Silva AC, Silva-Vergara ML, et al. (2011) Benign and malignant neoplasias in 261 necropsies for HIV-positive patients in the period of 1989 to 2008. Rev Inst Med Trop Sao Paulo 53: 309–314. 22183453

46. Sica A, Larghi P, Mancino A, Rubino L, Porta C, et al. (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18: 349–355. doi: 10.1016/j.semcancer.2008.03.004 18467122

47. Feng P, Scott CW, Cho NH, Nakamura H, Chung YH, et al. (2004) Kaposi's sarcoma-associated herpesvirus K7 protein targets a ubiquitin-like/ubiquitin-associated domain-containing protein to promote protein degradation. Mol Cell Biol 24: 3938–3948. 15082787

48. Feng P, Everly DN Jr., Read GS (2001) mRNA decay during herpesvirus infections: interaction between a putative viral nuclease and a cellular translation factor. J Virol 75: 10272–10280. 11581395

49. Izumiya Y, Kobayashi K, Kim KY, Pochampalli M, Izumiya C, et al. (2013) Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation. PLoS Pathog 9: e1003506. doi: 10.1371/journal.ppat.1003506 23990779

50. Paden CR, Forrest JC, Tibbetts SA, Speck SH (2012) Unbiased mutagenesis of MHV68 LANA reveals a DNA-binding domain required for LANA function in vitro and in vivo. PLoS Pathog 8: e1002906. doi: 10.1371/journal.ppat.1002906 22969427

51. He S, Zhao J, Song S, He X, Minassian A, et al. (2015) Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production. Mol Cell 58: 134–146. doi: 10.1016/j.molcel.2015.01.036 25752576

52. Feng P, Park J, Lee BS, Lee SH, Bram RJ, et al. (2002) Kaposi's sarcoma-associated herpesvirus mitochondrial K7 protein targets a cellular calcium-modulating cyclophilin ligand to modulate intracellular calcium concentration and inhibit apoptosis. J Virol 76: 11491–11504. 12388711

53. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, et al. (2013) IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A 110: 11139–11144. doi: 10.1073/pnas.1219829110 23771900

54. Smith GA, Enquist LW (1999) Construction and transposon mutagenesis in Escherichia coli of a full-length infectious clone of pseudorabies virus, an alphaherpesvirus. J Virol 73: 6405–6414. 10400733

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#