[en] Alcelaphine herpesvirus 1 (AlHV-1) is a c-herpesvirus (c-HV) carried asymptomatically by wildebeest. Upon cross-species transmission, AlHV-1 induces a fatal lymphoproliferative disease named malignant catarrhal fever (MCF) in many ruminants, including cattle, and the rabbit model. Latency has been shown to be essential for MCF induction. However, the mechanisms causing the activation and proliferation of infected CD8+T cells are unknown. Many c-HVs express microRNAs (miRNAs). These small non-coding RNAs can regulate expression of host or viral target genes involved in various pathways and are thought to facilitate viral infection and/or mediate activation and proliferation of infected lymphocytes. The AlHV-1 genome has been predicted to encode a large number of miRNAs. However, their precise contribution in viral infection and pathogenesis in vivo remains unknown. Here, using cloning and sequencing of small RNAs we identified 36 potential miRNAs expressed in a lymphoblastoid cell line propagated from a calf infected with AlHV-1 and developing MCF. Among the sequenced candidate miRNAs, 32 were expressed on the reverse strand of the genome in two main clusters. The expression of these 32 viral miRNAs was further validated using Northern blot and quantitative reverse transcription PCR in lymphoid organs of MCF- developing calves or rabbits. To determine the concerted contribution in MCF of 28 viral miRNAs clustered in the non-protein-coding region of the AlHV-1 genome, a recombinant virus was produced. The absence of these 28 miRNAs did not affect viral growth in vitro or MCF induction in rabbits, indicating that the AlHV-1 miRNAs clustered in this non-protein-coding genomic region are dispensable for MCF induction.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Sorel, Océane ; Université de Liège > Immunologie et vaccinologie
Balcells, I., Cirera, S. & Busk, P. K. (2011). Specific and sensitive quantitative RT-PCR of miRNAs with DNA primers. BMC Biotechnol 11, 70.
Bartel, D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233.
Barton, E., Mandal, P. & Speck, S. H. (2011). Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29, 351-397.
Busk, P. K. (2014). A tool for design of primers for microRNAspecific quantitative RT-qPCR. BMC Bioinformatics 15, 29.
Buxton, D. & Reid, H. W. (1980). Transmission of malignant catarrhal fever to rabbits. Vet Rec 106, 243-245.
Chen, Y., Liersch, R. & Detmar, M. (2012). The miR-290-295 cluster suppresses autophagic cell death of melanoma cells. Sci Rep 2, 808.
Croce, C. M. (2009). Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10, 704-714.
Dewals, B. G. & Vanderplasschen, A. (2011). Malignant catarrhal fever induced by Alcelaphine herpesvirus 1 is characterized by an expansion of activated CD3+CD8+CD4−T cells expressing a cytotoxic phenotype in both lymphoid and non-lymphoid tissues. Vet Res 42, 95.
Dewals, B., Boudry, C., Gillet, L., Markine-Goriaynoff, N., de Leval, L., Haig, D. M. & Vanderplasschen, A. (2006). Cloning of the genome of Alcelaphine herpesvirus 1 as an infectious and pathogenic bacterial artificial chromosome. J Gen Virol 87, 509-517.
Dewals, B., Boudry, C., Farnir, F., Drion, P. V. & Vanderplasschen, A. (2008). Malignant catarrhal fever induced by alcelaphine herpesvirus 1 is associated with proliferation of CD8+T cells supporting a latent infection. PLoS One 3, e1627.
Dewals, B., Myster, F., Palmeira, L., Gillet, L., Ackermann, M. & Vanderplasschen, A. (2011). Ex vivo bioluminescence detection of Alcelaphine herpesvirus 1 infection during malignant catarrhal fever. J Virol 85, 6941-6954.
Diebel, K. W., Oko, L. M., Medina, E. M., Niemeyer, B. F., Warren, C. J., Claypool, D. J., Tibbetts, S. A., Cool, C. D., Clambey, E. T. & van Dyk, L. F. (2015). Gammaherpesvirus small noncoding RNAs are bifunctional elements that regulate infection and contribute to virulence in vivo. MBio 6, e01670-e01714.
Dölken, L., Krmpotic, A., Kothe, S., Tuddenham, L., Tanguy, M., Marcinowski, L., Ruzsics, Z., Elefant, N., Altuvia, Y. & other authors (2010). Cytomegalovirus microRNAs facilitate persistent virus infection in salivary glands. PLoS Pathog 6, e1001150.
Ensser, A. & Fleckenstein, B. (2005). T-cell transformation and oncogenesis by c2-herpesviruses. Adv Cancer Res 93, 91-128.
Ensser, A., Pflanz, R. & Fleckenstein, B. (1997). Primary structure of the alcelaphine herpesvirus 1 genome. J Virol 71, 6517-6525.
Feederle, R., Linnstaedt, S. D., Bannert, H., Lips, H., Bencun, M., Cullen, B. R. & Delecluse, H. J. (2011). A viral microRNA cluster strongly potentiates the transforming properties of a human herpesvirus. PLoS Pathog 7, e1001294.
Feldman, E. R., Kara, M., Coleman, C. B., Grau, K. R., Oko, L. M., Krueger, B. J., Renne, R., van Dyk, L. F. & Tibbetts, S. A. (2014). Virus-encoded microRNAs facilitate gammaherpesvirus latency and pathogenesis in vivo. MBio 5, e00981-e001014.
Gottwein, E., Mukherjee, N., Sachse, C., Frenzel, C., Majoros, W. H., Chi, J. T., Braich, R., Manoharan, M., Soutschek, J. & other authors (2007). A viral microRNA functions as an orthologue of cellular miR-155. Nature 450, 1096-1099.
Grey, F. (2015). Role of microRNAs in herpesvirus latency and persistence. J Gen Virol 96, 739-751.
Kincaid, R. P. & Sullivan, C. S. (2012). Virus-encoded microRNAs: an overview and a look to the future. PLoS Pathog 8, e1003018.
Liu, P., Jenkins, N. A. & Copeland, N. G. (2003). A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res 13, 476-484.
Lüningschrör, P., Stöcker, B., Kaltschmidt, B. & Kaltschmidt, C. (2012). miR-290 cluster modulates pluripotency by repressing canonical NF-κ B signaling. Stem Cells 30, 655-664.
Nightingale, K., Levy, C. S., Hopkins, J., Grey, F., Esper, S. & Dalziel, R. G. (2014). Expression of ovine herpesvirus-2 encoded microRNAs in an immortalised bovine - cell line. PLoS One 9, e97765.
Palmeira, L., Sorel, O., Van Campe, W., Boudry, C., Roels, S., Myster, F., Reschner, A., Coulie, P. G., Kerkhofs, P. & other authors (2013). An essential role for γ-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle. Proc Natl Acad Sci U S A 110, E1933-E1942.
Pfeffer, S., Zavolan, M., Grässer, F. A., Chien, M., Russo, J. J., Ju, J., John, B., Enright, A. J., Marks, D. & other authors (2004). Identification of virus-encoded microRNAs. Science 304, 734-736.
Pfeffer, S., Sewer, A., Lagos-Quintana, M., Sheridan, R., Sander, C., Grässer, F. A., van Dyk, L. F., Ho, C. K., Shuman, S. & other authors (2005). Identification of microRNAs of the herpesvirus family. Nat Methods 2, 269-276.
Plowright, W. I. (1965a). Malignant catarrhal fever in East Africa. I. Behaviour of the virus in free-living populations of blue wildebeest (Gorgon taurinus taurinus Burchell). Res Vet Sci 6, 56-68.
Plowright, W. (1965b). Malignant catarrhal fever in East Africa. II. Observations on wildebeest calves at the laboratory and contact transmission of the infection to cattle. Res Vet Sci 6, 69-83.
Plowright, W. (1990). Malignant catarrhal fever virus. In Virus Infections of Ruminants, pp. 123-150. Edited by Z. Dinter & B. Morein. Amsterdam: Elsevier.
Plowright, W., Ferris, R. D. & Scott, G. R. (1960). Blue wildebeest and the aetiological agent of bovine malignant catarrhal fever. Nature 188, 1167-1169.
Plowright, W., Herniman, K. A., Jessett, D. M., Kalunda, M. & Rampton, C. S. (1975). Immunisation of cattle against the herpesvirus of malignant catarrhal fever: failure of inactivated culture vaccines with adjuvant. Res Vet Sci 19, 159-166.
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. J Gen Virol 95, 472-480.
Rosewick, N., Momont, M., Durkin, K., Takeda, H., Caiment, F., Cleuter, Y., Vernin, C., Mortreux, F., Wattel, E. & other authors (2013). Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma. Proc Natl Acad Sci U S A 110, 2306-2311.
Russell, G. C., Stewart, J. P. & Haig, D. M. (2009). Malignant catarrhal fever: a review. Vet J 179, 324-335.
Seto, E., Moosmann, A., Grömminger, S., Walz, N., Grundhoff, A. & Hammerschmidt, W. (2010). Micro RNAs of Epstein-Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog 6, e1001063.
Stik, G., Laurent, S., Coupeau, D., Coutaud, B., Dambrine, G., Rasschaert, D. & Muylkens, B. (2010). A p53-dependent promoter associated with polymorphic tandem repeats controls the expression of a viral transcript encoding clustered microRNAs. RNA 16, 2263-2276.
Suffert, G., Malterer, G., Hausser, J., Viiliäinen, J., Fender, A., Contrant, M., Ivacevic, T., Benes, V., Gros, F. & other authors (2011). Kaposi’s sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis. PLoS Pathog 7, e1002405.
Swa, S., Wright, H., Thomson, J., Reid, H. & Haig, D. (2001). Constitutive activation of Lck and Fyn tyrosine kinases in large granular lymphocytes infected with the c-herpesvirus agents of malignant catarrhal fever. Immunology 102, 44-52.
Tuddenham, L., Jung, J.S., Chane-Woon-Ming, B., Dölken, L. & Pfeffer, S. (2012).S mall RNA deep sequencing identifiesmicroRNAs and other small noncoding RNAs from human herpesvirus 6B. J Virol 86, 1638-1649.
Ventura, A. & Jacks, T. (2009). MicroRNAs and cancer: short RNAs go a long way. Cell 136, 586-591.
Walz, A., Feinstein, P., Khan, M. & Mombaerts, P. (2007). Axonal wiring of guanylate cyclase-D-expressing olfactory neurons is dependent on neuropilin 2 and semaphorin 3F. Development 134, 4063-4072.
Walz, N., Christalla, T., Tessmer, U. & Grundhoff, A. (2010). A global analysis of evolutionary conservation among known and predicted gammaherpesvirus microRNAs. J Virol 84, 716-728.
Warming, S., Costantino, N., Court, D. L., Jenkins, N. A. & Copeland, N. G. (2005). Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33, e36.
Zhao, Y., Yao, Y., Xu, H., Lambeth, L., Smith, L. P., Kgosana, L., Wang, X. & Nair, V. (2009). A functional microRNA-155 ortholog encoded by the oncogenic Marek’s disease virus. J Virol 83, 489-492.
Zhao, Y., Xu, H., Yao, Y., Smith, L. P., Kgosana, L., Green, J., Petherbridge, L., Baigent, S. J. & Nair, V. (2011). Critical role of the virus-encoded microRNA-155 ortholog in the induction of Marek’s disease lymphomas. PLoS Pathog 7, e1001305.
Zhu, Y., Haecker, I., Yang, Y., Gao, S. J. & Renne, R. (2013). γ-Herpesvirus-encoded miRNAs and their roles in viral biology and pathogenesis. Curr Opin Virol 3, 266-275.
Zuker, M. (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31, 3406-3415.