Oncogenic Potential of Ovine Herpesvirus 2 and Its Molecular Homology with Epstein–Barr Virus
DOI:
https://doi.org/10.14738/ejas.1404.11992Keywords:
Ovine herpesvirus 2, malignant catarrhal fever, Epstein-Barr virus, Burkitt's lymphoma, glycoprotein B, electron microscopy, gammaherpesvirus, oncogenesisAbstract
Ovine herpesvirus 2 (OvHV-2) causes malignant catarrhal fever (MCF), a lymphoproliferative disease that is often fatal and economically important in cattle and many other susceptible artiodactyls. However, its ability to cause cancer, and its relationship to Epstein-Barr virus (EBV), the classic human tumour gammaherpesvirus, is still unclear. In this study, we combined a critical review of the molecular biology of both viruses with new findings from an Egyptian OvHV-2 isolate to test whether OvHV-2 shares the tumour-forming architecture of EBV. Tongue-mucosa supernatant from a confirmed Egyptian MCF case, previously characterised by complete glycoprotein B (gB) gene sequencing, was examined by negative-staining transmission electron microscopy (TEM) and grown in specific pathogen-free embryonated chicken eggs through the chorioallantoic membrane (CAM) route. TEM showed morphology typical of Burkitt's lymphoma, and CAM growth produced distinct tumours, indicating that OvHV-2 can transform cells even in a non-mammalian host. The comparison showed broad homology between the two viruses, including conserved viral BCL-2, interleukin-10 and BILF1 G-protein-coupled-receptor homologues. The OvHV-2 gB sequence was 99-100% identical to reference genomes and remained stable after passage in cell lines. These results suggest that OvHV-2 is the veterinary equivalent of EBV, with cross-species and possibly zoonotic importance, and raise the possibility that the two are the same virus. We recommend electron microscopy supported by gB sequencing as a rapid first-line diagnostic, and urge screening of cell cultures and a wide range of hosts. For control, we propose OvHV-2 gB subunit vaccination and anti-gB camelid nanobody treatments, and the removal of animal-origin additives from animal feed.
References
AlHajri, S. M., Cunha, C. W., Nicola, A. V., Aguilar, H. C., Li, H., & Taus, N. S. (2017). Ovine herpesvirus 2 glycoproteins B, H, and L are sufficient for, and viral glycoprotein Ov8 can enhance, cell-cell membrane fusion. Journal of Virology, 91(5), e02454-16. https://doi.org/10.1128/JVI.02454-16
Al-Khreisat, M. J., Ismail, N. H., Tabnjh, A., Hussain, F. A., Mohamed Yusoff, A. A., Johan, M. F., & Islam, M. A. (2023). Worldwide prevalence of Epstein-Barr virus in patients with Burkitt lymphoma: A systematic review and meta-analysis. Diagnostics, 13(12), 2068. https://doi.org/10.3390/diagnostics13122068
Anderson, I. E., Deane, D., Swa, S., Thomson, J., Campbell, I., Buxton, D., Wei, X.-Q., Stewart, J. P., Russell, G. C., & Haig, D. M. (2008). Production and utilization of interleukin-15 in malignant catarrhal fever. Journal of Comparative Pathology, 138(2-3), 131-144. https://doi.org/10.1016/j.jcpa.2008.01.002
Andriyanov, P. A., Zakharova, O. I., Zhurilov, P. A., Tutrina, A. I., Kashina, D. D., Burova, O. A., Liskova, E. A., Shirokova, E. A., Yashin, I. V., & Blokhin, A. A. (2025). Clinical, pathological, and molecular aspects of malignant catarrhal fever in Russia: A case report. Veterinary Research Communications, 49(4), 189. https://doi.org/10.1007/s11259-025-10758-0
Babcock, G. J., Decker, L. L., Volk, M., & Thorley-Lawson, D. A. (1998). EBV persistence in memory B cells in vivo. Immunity, 9(3), 395-404. https://doi.org/10.1016/S1074-7613(00)80622-6
Baer, R., Bankier, A. T., Biggin, M. D., Deininger, P. L., Farrell, P. J., Gibson, T. J., Hatfull, G., Hudson, G. S., Satchwell, S. C., Seguin, C., Tuffnell, P. S., & Barrell, B. G. (1984). DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature, 310(5974), 207-211. https://doi.org/10.1038/310207a0
Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116(2), 281-297. https://doi.org/10.1016/S0092-8674(04)00045-5
Bastawecy, I. M. (2021). Mode of infection and some diseases caused by Epstein-Barr virus: The most ubiquitous, common malignant and characteristic virus. Journal of Human Virology & Retrovirology, 9(1), 6-9. https://doi.org/10.15406/jhvrv.2021.09.00237
Bastawecy , I.M. (2022) : Electron microscopy as a differential diagnosis technique : serving in the diagnosis of malignant catarrhal fever in farm animals . Journal of American Science , 18 (9) . https://doi.org/10.7537/marsjas180922.06.
Bastawecy, I. M.,&Abd El-Samee, A. A. (2012). First isolation and identification of ovine herpesvirus 2 causing malignant catarrhal fever outbreak in Egypt. Life Science Journal, 9, 798-804.
Bastawecy, I. M., Abdelmonem, M., Afify, A. F., Saad, N., Shirosaki, Y., Abdullah, C. A. C., El Naggar, R. F., Rohaim, M. A., & Munir, M. (2025). Viral contamination in cell culture: Analyzing the impact of Epstein-Barr virus and Ovine herpesvirus 2. Frontiers in Microbiology, 16, 1442321. https://doi.org/10.3389/fmicb.2025.1442321
Scholar Publishing Bastawecy, I. M., El Damaty, H. M., Fawzi, E. M.,&El-Said, H. M. (2015). Ovine herpesvirus 2 can cause skin lesions in susceptible animals. Journal of American Science, 11(2), 102-107.
Baxter, S. I. F., Pow, I., Bridgen, A., & Reid, H. W. (1993). PCR detection of the sheep-associated agent of malignant catarrhal fever. Archives of Virology, 132(1-2), 145-159. https://doi.org/10.1007/BF01309849
Beisser, P. S., Verzijl, D., Gruijthuijsen, Y. K., Beuken, E., Smit, M. J., Leurs, R., Bruggeman, C. A., & Vink, C. (2005). The Epstein-Barr virus BILF1 gene encodes a G protein-coupled receptor that inhibits phosphorylation of RNA-dependent protein kinase. Journal of Virology, 79(1), 441-449. https://doi.org/10.1128/JVI.79.1.441-449.2005
Bellows, D. S., Howell, M., Pearson, C., Hazlewood, S. A., & Hardwick, J. M. (2002). Epstein-Barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins. Journal of Virology, 76(5), 2469-2479. https://doi.org/10.1128/JVI.76.5.2469-2479.2002
Bianchessi, L., Flach, E., Monacchia, G., Dagleish, M., Maley, M., Turin, L., & Rocchi, M. S. (2024). Identification and characterisation of gamma-herpesviruses in zoo artiodactyla. Virology Journal, 21, 49. https://doi.org/10.1186/s12985-024-02311-3
Brady, G., MacArthur, G. J., & Farrell, P. J. (2007). Epstein-Barr virus and Burkitt lymphoma. Journal of Clinical Pathology, 60(12), 1397-1402. https://doi.org/10.1136/jcp.2007.047977
Cannarile, M. A., Weisser, M., Jacob, W., Jegg, A.-M., Ries, C. H., & Ruttinger, D. (2017). Colonystimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. Journal for ImmunoTherapy of Cancer, 5(1), 53. https://doi.org/10.1186/s40425-017-0257-y
Cohen, J. I. (2000). Epstein-Barr virus infection. New England Journal of Medicine, 343(7), 481-492. https://doi.org/10.1056/NEJM200008173430707
Coskun, O., Sener, K., Kilic, S., Erdem, H., Yaman, H., Besirbellioglu, A. B., Gul, H. C., & Eyigun, C. P. (2010). Stress-related Epstein-Barr virus reactivation. Clinical and Experimental Medicine, 10(1), 15-20. https://doi.org/10.1007/s10238-009-0063-z
Coulter, L. J., & Reid, H. W. (2002). Isolation and expression of three open reading frames from ovine herpesvirus-2. Journal of General Virology, 83(3), 533-543. https://doi.org/10.1099/0022-1317-83-3-533
Cunha, C. W., Baker, K. N., O'Toole, D., Cole, E., Shringi, S., Dewals, B. G., Vanderplasschen, A., & Li, H. (2022). A vaccine targeting ovine herpesvirus 2 glycoprotein B protects against sheepassociated malignant catarrhal fever. Vaccines, 10(12), 2156. https://doi.org/10.3390/vaccines10122156
Cunha, C. W., Slater, O. M., Macbeth, B., Duignan, P. J., Warren, A., Highland, M. A., & Li, H. (2019). Domestic sheep and bighorn sheep carry distinct gammaherpesviruses belonging to the genus Macavirus. Virus Research, 272, 197729. https://doi.org/10.1016/j.virusres.2019.197729
Cyprian, F. S., Al-Farsi, H. F., Vranic, S., Akhtar, S., & Al Moustafa, A.-E. (2018). Epstein-Barr virus and human papillomaviruses interactions and their roles in the initiation of epithelial-mesenchymal transition and cancer progression. Frontiers in Oncology, 8, 111. https://doi.org/10.3389/fonc.2018.00111
Damania, B., Kenney, S. C., & Raab-Traub, N. (2022). Epstein-Barr virus: Biology and clinical disease. Cell, 185(20), 3652-3670. https://doi.org/10.1016/j.cell.2022.08.026
de Martel, C., Georges, D., Bray, F., Ferlay, J., & Clifford, G. M. (2020). Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis. The Lancet Global Health, 8(2), e180-e190. https://doi.org/10.1016/S2214-109X(19)30488-7
Scholar Publishing de Munnik, S. M., Smit, M. J., & Vischer, H. F. (2015). Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors. Frontiers in Pharmacology, 6, 40. https://doi.org/10.3389/fphar.2015.00040
De Re, V., Caggiari, L., De Zorzi, M., Fanotto, V., Miolo, G., Puglisi, F., Cannizzaro, R., Canzonieri, V., Steffan, A., Farruggia, P., Lopci, E., d'Amore, E. S. G., Burnelli, R., Mussolin, L., & Mascarin, M. (2020). Epstein-Barr virus BART microRNAs in EBV-associated Hodgkin lymphoma and gastric cancer. Infectious Agents and Cancer, 15, 42. https://doi.org/10.1186/s13027-020-00307-6
El-Sharkawy, A., Al Zaidan, L., & Malki, A. (2018). Epstein-Barr virus-associated malignancies: Roles of viral oncoproteins in carcinogenesis. Frontiers in Oncology, 8, 265. https://doi.org/10.3389/fonc.2018.00265
Epstein, M. A., Achong, B. G., & Barr, Y. M. (1964). Virus particles in cultured lymphoblasts from Burkitt's lymphoma. The Lancet, 283(7335), 702-703. https://doi.org/10.1016/S0140-6736(64)91524-7
Glaser, R., Pearson, G. R., Jones, J. F., Hillhouse, J., Kennedy, S., Mao, H., & Kiecolt-Glaser, J. K. (1991). Stress-related activation of Epstein-Barr virus. Brain, Behavior, and Immunity, 5(2), 219-232. https://doi.org/10.1016/0889-1591(91)90018-6
Goldsmith, C. S., & Miller, S. E. (2009). Modern uses of electron microscopy for detection of viruses. Clinical Microbiology Reviews, 22(4), 552-563. https://doi.org/10.1128/CMR.00027-09
Hart, J., Ackermann, M., Jayawardane, G., Russell, G., Haig, D. M., Reid, H., & Stewart, J. P. (2007). Complete sequence and analysis of the ovine herpesvirus 2 genome. Journal of General Virology, 88(1), 28-39. https://doi.org/10.1099/vir.0.82284-0
Hazelton, P. R., & Gelderblom, H. R. (2003). Electron microscopy for rapid diagnosis of emerging infectious agents. Emerging Infectious Diseases, 9(3), 294-303. https://doi.org/10.3201/eid0903.020327
Headley, S. A., Dall Agnol, A. M., Bessegato, J. A., Frucchi, A. P. S., Maturana, E. F. L., Rodrigues, R. V., Xavier, A. A. C., Alfieri, A. F., & Alfieri, A. A. (2023). Association of ovine gammaherpesvirus 2 with an outbreak of acute respiratory disease in dairy cattle. Scientific Reports, 13, 5623. https://doi.org/10.1038/s41598-023-30133-w
Headley, S. A., Fritzen, J. T. T., Rodriguez, M. C., & Alfieri, A. A. (2024). Quantification of ovine gammaherpesvirus 2 in clinical cases of cattle with sheep-associated malignant catarrhal fever. Brazilian Journal of Microbiology, 55(2), 1949-1959. https://doi.org/10.1007/s42770-024-01357-3
Jayawardane, G., Russell, G. C., Thomson, J., Deane, D., Cox, H., Gatherer, D., Ackermann, M., Haig, D. M., & Stewart, J. P. (2008). A captured viral interleukin 10 gene with cellular exon structure. Journal of General Virology, 89(10), 2447-2455. https://doi.org/10.1099/vir.0.2008/001743-0
Kvansakul, M., Wei, A. H., Fletcher, J. I., Willis, S. N., Chen, L., Roberts, A. W., Huang, D. C. S., & Colman, P. M. (2010). Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1. PLoS Pathogens, 6(12), e1001236. https://doi.org/10.1371/journal.ppat.1001236
Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843-854. https://doi.org/10.1016/0092-8674(93)90529-Y
Levitskaya, J., Coram, M., Levitsky, V., Imreh, S., Steigerwald-Mullen, P. M., Klein, G., Kurilla, M. G., & Masucci, M. G. (1995). Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature, 375(6533), 685-688. https://doi.org/10.1038/375685a0
Scholar Publishing Li, H., Cunha, C. W., & Taus, N. S. (2011). Malignant catarrhal fever: Understanding molecular diagnostics in context of epidemiology. International Journal of Molecular Sciences, 12(10), 6881-6893. https://doi.org/10.3390/ijms12106881
Liggitt, H. D., & DeMartini, J. C. (1980a). The pathomorphology of malignant catarrhal fever. I. Generalized lymphoid vasculitis. Veterinary Pathology, 17(1), 58-72.
Liggitt, H. D., & DeMartini, J. C. (1980b). The pathomorphology of malignant catarrhal fever. II. Multisystemic epithelial lesions. Veterinary Pathology, 17(1), 73-83.
Loken, T., Aleksandersen, M., Reid, H., & Pow, I. (1998). Malignant catarrhal fever caused by ovine herpesvirus-2 in pigs in Norway. Veterinary Record, 143(17), 464-467. https://doi.org/10.1136/vr.143.17.464
Lyngaa, R., Norregaard, K., Kristensen, M., Kubale, V., Rosenkilde, M. M., & Kledal, T. N. (2010). Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling. Oncogene, 29(31), 4388-4398. https://doi.org/10.1038/onc.2010.173
Madrigal-Valencia, T. L., Saavedra-Montanez, M., Perez-Torres, A., Hernandez, J., Segales, J., Dominguez Hernandez, Y., Candanosa-Aranda, I. E., Perez-Guiot, A., & Ramirez-Mendoza, H. (2023). First identification and characterization of ovine gammaherpesvirus type 2 in horses and artiodactyla from an outbreak of malignant catarrhal fever in Mexico. PLOS ONE, 18(9), e0290309. https://doi.org/10.1371/journal.pone.0290309
McGeoch, D. J., Cook, S., Dolan, A., Jamieson, F. E., & Telford, E. A. R. (1995). Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. Journal of Molecular Biology, 247(3), 443-458. https://doi.org/10.1006/jmbi.1995.0152
Meier-Trummer, C. S., Tobler, K., Hilbe, M., Stewart, J. P., Hart, J., Campbell, I., Haig, D. M., Glauser, D. L., Ehrensperger, F., & Ackermann, M. (2009). Ovine herpesvirus 2 structural proteins in epithelial cells and M-cells of the appendix in rabbits with malignant catarrhal fever. Veterinary Microbiology, 137(3-4), 235-242. https://doi.org/10.1016/j.vetmic.2009.01.030
Münz, C. (2019). Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nature Reviews Microbiology, 17(11), 691-700. https://doi.org/10.1038/s41579-019-0249-7
Münz, C. (2025). Epstein-Barr virus pathogenesis and emerging control strategies. Nature Reviews Microbiology, 23(10), 667-679. https://doi.org/10.1038/s41579-025-01181-y
O'Toole, D., & Li, H. (2014). The pathology of malignant catarrhal fever, with an emphasis on ovine herpesvirus 2. Veterinary Pathology, 51(2), 437-452. https://doi.org/10.1177/0300985813520435
O'Toole, D., Li, H., Sourk, C., Montgomery, D. L., & Crawford, T. B. (2002). Malignant catarrhal fever in a bison (Bison bison) feedlot, 1993-2000. Journal of Veterinary Diagnostic Investigation, 14(3), 183-193. https://doi.org/10.1177/104063870201400301
Paulsen, S. J., Rosenkilde, M. M., Eugen-Olsen, J., & Kledal, T. N. (2005). Epstein-Barr virusencoded BILF1 is a constitutively active G protein-coupled receptor. Journal of Virology, 79(1), 536-546. https://doi.org/10.1128/JVI.79.1.536-546.2005
Pfeffer, S., Zavolan, M., Grasser, F. A., Chien, M., Russo, J. J., Ju, J., John, B., Enright, A. J., Marks, D., Sander, C., & Tuschl, T. (2004). Identification of virus-encoded microRNAs. Science, 304(5671), 734-736. https://doi.org/10.1126/science.1096781
Pinheiro de Oliveira, T. F., Laguardia-Nascimento, M., Xavier, F. G., do Amaral Pinto, C., Ferreira, L. R., de Castro Campos de Souza, I., Hammerschmitt, M. E., Bianchi, R. M., Wronski, J. G., Etges, Scholar Publishing R. N., Rigon, G. M., Camargos, M. F., Rodrigues Junior, A. V., & Fonseca Junior, A. A. (2019). Quantification of ovine herpesvirus 2 by digital PCR in an outbreak of malignant catarrhal fever. Archives of Virology, 164(12), 3045-3050. https://doi.org/10.1007/s00705-019-04382-y
Riaz, A., Dry, I., Levy, C. S., Hopkins, J., Grey, F., Shaw, D. J., & Dalziel, R. G. (2014). Ovine herpesvirus-2-encoded microRNAs target virus genes involved in virus latency. Journal of General Virology, 95(2), 472-480. https://doi.org/10.1099/vir.0.059303-0
Riaz, A., Dry, I., Dalziel, R., Rehman, S. U., Shah, M. A., Akhtar, H. M. N., Yousaf, A., & Baig, R. (2021). Molecular detection and characterization of ovine herpesvirus-2 using heminested PCR in Pakistan. Journal of Veterinary Science, 22(4), e51. https://doi.org/10.4142/jvs.2021.22.e51
Rosato, G., Ruiz Subira, A., Al-Saadi, M., Michalopoulou, E., Verin, R., Dettwiler, M., Nordgren, H., Chiers, K., Grossmann, E., Kohler, K., Suntz, M., Stewart, J. P., & Kipar, A. (2021). Gammaherpesvirus infections in cattle in Europe. Viruses, 13(12), 2337. https://doi.org/10.3390/v13122337
Russell, G. C., Stewart, J. P., & Haig, D. M. (2009). Malignant catarrhal fever: A review. The Veterinary Journal, 179(3), 324-335. https://doi.org/10.1016/j.tvjl.2007.11.007
Shrestha, N., Tobler, K., Uster, S., Sigrist-Nagy, R., Hierweger, M. M., & Ackermann, M. (2020). Ovine herpesvirus 2 encodes a previously unrecognized protein, pOv8.25, that targets mitochondria and triggers apoptotic cell death. Journal of Virology, 94(8), e01536-19. https://doi.org/10.1128/JVI.01536-19
Simon, S., Li, H., O'Toole, D., Crawford, T. B., & Oaks, J. L. (2003). The vascular lesions of a cow and bison with sheep-associated malignant catarrhal fever contain ovine herpesvirus 2-infected CD8+ T lymphocytes. Journal of General Virology, 84(8), 2009-2013. https://doi.org/10.1099/vir.0.19048-0
Siscovick, D. S., Barringer, T. A., Fretts, A. M., Wu, J. H. Y., Lichtenstein, A. H., Costello, R. B., Kris-Etherton, P. M., Jacobson, T. A., Engler, M. B., Alger, H. M., Appel, L. J., & Mozaffarian, D. (2017). Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: A science advisory from the American Heart Association. Circulation, 135(15), e867-e884. https://doi.org/10.1161/CIR.0000000000000482
Strockbine, L. D., Cohen, J. I., Farrah, T., Lyman, S. D., Wagener, F., DuBose, R. F., Armitage, R. J., & Spriggs, M. K. (1998). The Epstein-Barr virus BARF1 gene encodes a novel, soluble colonystimulating factor-1 receptor. Journal of Virology, 72(5), 4015-4021. https://doi.org/10.1128/JVI.72.5.4015-4021.1998
Taus, N. S., Oaks, J. L., Gailbreath, K., Traul, D. L., O'Toole, D., & Li, H. (2006). Experimental aerosol infection of cattle (Bos taurus) with ovine herpesvirus 2 using nasal secretions from infected sheep. Veterinary Microbiology, 116(1-3), 29-36. https://doi.org/10.1016/j.vetmic.2006.03.005
Thonur, L., Russell, G. C., Stewart, J. P., & Haig, D. M. (2006). Differential transcription of ovine herpesvirus 2 genes in lymphocytes from reservoir and susceptible species. Virus Genes, 32(1), 27-35. https://doi.org/10.1007/s11262-005-5842-3
Trzaskowski, B., Latek, D., Yuan, S., Ghoshdastider, U., Debinski, A., & Filipek, S. (2012). Action of molecular switches in GPCRs - theoretical and experimental studies. Current Medicinal Chemistry, 19(8), 1090-1109. https://doi.org/10.2174/092986712799320556
Tsutsumi, N., Qu, Q., Mavri, M., Baggesen, M. S., Maeda, S., Waghray, D., Berg, C., Kobilka, B. K., Rosenkilde, M. M., Skiniotis, G., & Garcia, K. C. (2021). Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1. Immunity, 54(7), 1405-1416.e7. https://doi.org/10.1016/j.immuni.2021.06.001 Scholar Publishing
Wang, L., & Ning, S. (2021). New look of EBV LMP1 signaling landscape. Cancers, 13(21), 5451. https://doi.org/10.3390/cancers13215451
Zaki, A. A. M., El-Said, H. M., Abd El-Aziz, A., Bastawecy, I. M., Abd El-Wahab, S. A.,&El-Sayed, M. M. (2016). Field study on malignant catarrhal fever (MCF) in Egypt. Life Science Journal, 13, 83-97.
Zhang, Z., Schwartz, S., Wagner, L., & Miller, W. (2000). A greedy algorithm for aligning DNA sequences. Journal of Computational Biology, 7(1-2), 203-214.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Iman M. Bastawecy, Morcos I. Yanni, Fatima-Alzahraa Gamal, Mohamed Abdelmonem
This work is licensed under a Creative Commons Attribution 4.0 International License.
