Pathogenesis of MHV-68

A major focus of our group is on the molecular virology of γ-herpesviruses which cause life-long persistent infections in humans and animals.

There are two human γ-herpesviruses, the Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), both of which establish latency in B lymphocytes. EBV is associated with infectious mononucleosis as well as numerous human tumours. KSHV infection is detectable in virtually all Kaposi's sarcomas and B-cell primary effusion lymphomas. The most important animal γ-herpesviruses are the related Alcelaphine herpesvirus-1 and Ovine herpesvirus-2 (OvHV-2) that are associated with a fatal lymphoproliferative disease of domestic cattle and deer called malignant catarrhal fever (MCF). Infection of mice with the murine γ-herpesvirus, MHV-68 has been developed as a small animal model system. This system has enabled the study of key aspects of γ-herpesvirus infection in a natural host, in particular the detailed study of the fundamentals of virus-host interactions.

Murine γ-herpesvirus (MHV-68) MHV-68 is a natural pathogen of free-living murid rodents such as wood mice. Mice inoculated intranasally with MHV-68 establish a productive infection in the lung in alveolar epithelial cells causing an interstitial and peri-bronchiolar pneumonia. This productive phase of infection lasts for around 10 days, during which period the virus spreads via lymph nodes to the spleen. Here it establishes latency predominantly in B cells. This initial latent infection in the spleen causes an intense lymphoproliferation of B cells and T cells alike leading to splenomegaly. Although the precise mechanisms underlying splenomegaly are still being elucidated, it is clear that infected B cells and CD4+ 'helper' T cells are critical. Also, it is clear that a number of cytokines are secreted in abundance and this cytokine 'storm' almost certainly contributes towards driving lymphoproliferation. Latently infected cells appear in the first week post-infection, reach peak levels during the second to third week before declining to a basal level (1 in a million leukocytes) that is maintained indefinitely in the host. Like most virus infections, T cells are critical for the immune-mediated resolution of infection. An important finding of this laboratory is that the spleen is not the only site of latency and that MHV-68 also persists indefinitely in lungs.

The MHV-68 genome has 118kb of largely unique DNA flanked by terminal repeats and its complete DNA sequence has been determined recently. Of the 80 or so open-reading frames (ORFs) found, most are homologous to other g-herpesvirus or cellular genes. However, there are a number of ORFs, termed M1-4 that are unique, that is they have no obvious sequence relationship to virus or cellular genes recorded in current sequence databases.

The diagram above shows the the route of infection with MHV-68. The virus causes mainly lytic infection in lungs. This is cleared by cells of the immune system by 14 days after initial infection. However,the virus persists as a life-long latent infection mainly in B cells in lymphoid tissues.

The Stewart group has identified the role of a number of MHV-68 proteins during virus infection and discovered novel host proteins that are involved in host defence. More recently, we have developed the use of wood mice as a natural hsot system for MHV-68. This is helping to define the roles of a number of pathogenesis-realted virus proteins. Outputs from these projects are detailed below

    2012

  • Stevens, H.C., Cham, K. S-W., Hughes, D.J., Sun, R., Sample, J.T., Bubb, V.J., Stewart, J.P.* and Quinn, J.P. (2012). CTCF and SP1 interact with the murine gammaherpesvirus 68 internal repeat elements. Virus Genes, 45, 265-273.[Full Text on Publisher Website] [PDF]PDF *Corresponding author
  • Hughes, D.J., Kipar, A. Leeming, G., Sample, J.T. and Stewart, J.P. (2012). Experimental infection of laboratory-bred bank voles (Myodes glareolus) with Murid herepsvirus 4. Archives of Virology. 157, 2207 – 2212. DOI: 10.1007/s00705-012-1397-5 [PDF]PDF
  • 2011

  • Hughes, D.J., Kipar, A., Leeming, G.H., Bennett, E., Howarth, D., Cummerson, J.A., Papoula-Pereira, R., Flanagan, B.F., Sample, J.T., Stewart J.P. (2011). Chemokine Binding Protein M3 of Murine Gammaherpesvirus 68 Modulates the Host Response to Infection in a Natural Host. PLoS Pathogens, 7(3): e1001321. [Open Access Full Text] [PDF]PDF
  • *Cover image for March 2011 issue taken from this paper

  • Arico, E., Monque, D.M., D'Agostino, G., Moschella, F., Venditti, M., Kalinke, U., Allen, D.J., Stewart, J.P., Nash, A.A., Belardelli, F., Ferrantini, M. (2011). MHV-68 producing mIFNalpha1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68. Vaccine. 29, 3935-3944.[Full Text on Publisher Website] [PDF]PDF
  • Quinn, J.P., Kipar, A., Hughes, D.J., Bennett, E., Cox, H., McLaughlin, L., Zimmer, A., Hunt, S.P., and Stewart, J.P. (2011). Altered host response to murine gammaherpesvirus 68 infection in mice lacking the tachykinin 1 gene and the receptor for substance P. Neuropeptides. 45, 49-53. [Full Text on Publisher Website] [PDF]PDF
  • 2010

  • Steer, B., Adler, B., Jonjic, S., Stewart, J.P., Adler, H. (2010) A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB. PLoS One 5, e11672. [Open Access Full Text] [PDF]PDF
  • Hughes, D.J., Kipar, A., Sample, J.T., Stewart J.P. (2010). Pathogenesis of a model gammaherpesvirus in its natural host.  Journal of Virology. 84, 3949 - 3961. [Open Access Full Text] [PDF]PDF
  • Hughes, D.J., Kipar, A., Milligan, S., Cunningham, Saunders, M., Quail, M.A., Rajandream, M-A., Efstathiou, S., Bowden, R.J., Chastel, C., Bennett, M., Sample, J.T., Barrell, B., Davison, A.J. and Stewart, J.P. (2010). Characterization of a novel wood mouse virus related to murid herpesvirus 4. Journal of General Virology. 91, 867-879. [Open Access Full Text] [PDF]PDF
  • 2009

  • Ottinger, M., Pliquet, D., Christalla, T., Frank, R., Stewart, J.P., and Schulz, T.F. (2009). The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins is critical for the activation of cell cycle promoters. Journal of Virology. 83, 4423-4434. [Open Access Full Text] [PDF]PDF
  • Papoula-Pereira, R., Leeming, G., Hughes, D.J., Sample, J.T., Dutia, B.D., Stewart J.P. and Kipar, A. (2009). The role of M1 protein in the acute infection of wood mice with MHV-68 (Murid herpesvirus 4), Journal of Comparative Pathology, 141, 277. (Abstract)
  • 2008

  • Stewart J.P., Kipar, A., Cox, H., Payne, C., Vasiliou, S., Quinn, J.P. (2008). Induction of tachykinin production in airway epithelia in response to viral infection. PLoS ONE. 3, e1673. [Open Access Full Text] [PDF]PDF
  • 2007

  • Ehlers, B., Kuechler, J., Yasmum, N., Dural, G., Voigt, S., Schmidt-Chanasit, J., Jäkel, T., Matuschka, F.-R., Richter, D., Essbauer, S., Hughes, D.J., Summers, C., Bennett, M., Stewart, J.P., and Ulrich, R. (2007). Identification of novel rodent herpesviruses including the first Gammaherpesvirus of Mus musculus. Journal of Virology. 81, 8091-8100. [Open Access Full Text] [PDF]PDF
  • Becker, S.D., Bennett, M., Stewart, J.P. and Hurst, J.L. (2007). Serological survey of virus infection among wild house mice (Mus domesticus) in the UK. Laboratory Animals. 41, 229-238. [Open Access Full Text] [PDF]PDF
  • 2005

  • Stewart, J.P., Hughes, D.J., Roaden, L and Ebrahimi, B. (2005). Murid herpesvirus 4 as a model for gammaherpesvirus pathogenesis. In Molecular Pathogenesis of Virus Infections. Eds. Digard, P., Nash, A.A. and Randall, R.E. Cambridge University Press, Cambridge. pp 319-339. (Book Chapter).
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    2004

  • Obar, J.J., Donovan, D.C., Crist, S.G., Silvia, O.J., Stewart, J.P. and Usherwood, E.J.  (2004). T-Cell Responses to the M3 Immune Evasion Protein of Murid Gammaherpesvirus 68 Are Partially Protective and Induced with Lytic Antigen Kinetics. Journal of Virology. 78, 10829-10832. [Open Access Full Text] [PDF]PDF
  • Stewart, J.P., Silvia, O.J., Atkin, I.M.D., Hughes, D.J., Ebrahimi, B. and Adler, H. (2004). The in vivo function of a gammaherpesvirus virion glycoprotein: influence on B cell infection and mononucleosis. Journal of Virology. 78, 10449-10459. [Open Access Full Text] [PDF]PDF
  • Douglas, J., Dutia, B.M., Rhind,S., Stewart, J.P. and Talbot S.J. (2004) Expression in a recombinant murid herpesvirus 4 reveals the in vivo transforming potential of the K1 open reading frame of Kaposi's sarcoma associated herpesvirus (KSHV). Journal of Virology. 78, 8878-8884. [Open Access Full Text] [PDF]PDF
  • Dutia, B.M., Roy, D.J., Ebrahimi, B., Gangadharan, B., Efstathiou S., Stewart J.P. and Nash, A.A.  (2004). Identification of a region of the virus genome involved in murid gammaherpesvirus 68 induced splenic pathology. Journal of General Virology. 85, 1393-1400. [Open Access Full Text] [PDF]PDF
  • Verzijl, D., Fitzsimons, C.P., van Dijk, M., Stewart, J.P., Timmerman, H., Smit, M.J. and Leurs, R. (2004). Differential activation of murine herpesvirus 68- and Kaposi's sarcoma-associated herpesvirus-encoded ORF74 G protein-coupled receptors by human and murine chemokines. Journal of Virology. 78, 3343-3351. [Open Access Full Text] [PDF]PDF
  • 2003

  • Bortz, E., Whitelegge, J.P., Jia, Q., Atanasov, I., Zhou, Z.H., Stewart, J.P., Wu, T-T., and Sun, R. (2003). Identification of Proteins Associated with Murine Gammaherpesvirus-68 Virions. Journal of Virology. 77, 13425-13432. [Open Access Full Text] [PDF]PDF
  • Macrae, A.I., Usherwood, E.J., Husain, S.M., Flano, E., Kim, I-J., Woodland, D.J., Nash, A.A., Blackman, M.A., Sample, J.T. and Stewart, J.P. (2003). Murid Herpesvirus 4 Strain 68 M2 Protein is a B Cell-Associated Antigen Important for Latency but not Lymphocytosis. Journal of Virology. 77, 9700-9709. [Open Access Full Text] [PDF]PDF
  • Blasdell, K., McCracken, C., Morris, A., Nash, A.A., Begon, M., Bennett, M. and Stewart, J.P. (2003). The wood mouse is a natural host for Murid herpesvirus 4. Journal of General Virololgy. 84, 111-113. [Open Access Full Text] [PDF]PDF
  • Ebrahimi, B., Dutia, B.M., Roberts, K.L., Garcia-Ramirez, J.J., Stewart, J.P., Roy, D.J., Nash, A.A. (2003). Transcriptome profile of murine gammaherpesvirus-68 lytic infection. Journal of General Virology. 84, 99-109. [Open Access Full Text] [PDF]PDF
  • 2001

  • Payne, C.M., Heggie, C., Brownstein, D., Stewart, J.P., and Quinn, J.P.  (2001). Role of Tachykinins in the Host Response to Murine Gammaherpesvirus Infection. Journal of Virology, 75, 10467-10471. [Open Access Full Text] [PDF]PDF
  • Usherwood, E.J., Ward, K.A., Blackman, M.A., Stewart, J.P. and Woodland, D.L. (2001). Latent antigen vaccination in a model gammaherpesvirus infection. Journal of Virology. 75, 8283-8288. [Open Access Full Text] [PDF]PDF
  • Macrae, A.I., Dutia, B.M., Milligan, S., Allen, D.J., Brownstein, D.G., Mistrikova, J., Davison, A., Nash. A.A. and Stewart, J.P. (2001). Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis. Journal of Virology. 75, 5315-5327.  [Open Access Full Text] [PDF]PDF
  • Wakeling, M.N., Roy, D.J., Nash, A.A., Stewart, J.P. (2001). Characterization of the murine gammaherpesvirus ORF74 product – a novel oncogenic G-protein coupled receptor. Journal of General Virology. 82, 1187-1197. [Open Access Full Text] [PDF]PDF
  • Nash, A.A., Dutia, B.M., Stewart, J.P. and Davison, A.J. (2001). Natural history of murine gammaherpesvirus infection. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences.  356, 569-579. (Review). [PDF at Publisher Website] [PDF]PDF
  • 2000

  • Roy, D.J., Ebrahimi, B., Dutia, B.M., Nash, A.A. and Stewart, J.P. (2000). Murine gammaherpesvirus M11 gene product inhibits apoptosis and is expressed during virus persistence. Archives of Virology. 145, 2411-2420. [Full Text on Publisher Website] [PDF]PDF
  • Usherwood, E.J., Roy, D.J., Ward, K., Surman, S.L., Dutia, B.M., Blackman, M.A., Stewart, J.P. and Woodland, D.L. (2000). Control of gammaherpesvirus latency by latent antigen-specific CD8+ T cells. Journal of Experimental Medicine. 192, 943-952. [Open AccessFull Text] [PDF]PDF
  • Terry, L.A., Stewart, J.P., Nash, A.A. and Fazakerley, J.K. (2000). Murine gammaherpesvirus-68 infection of and persistence in the central nervous system. Journal of General Virology. 81, 2635-2643. [Open Access Full Text] [PDF]PDF
  • Wu, T-T., Usherwood, E.J., Stewart, J.P., Nash, A.A. and Sun, R. (2000). Rta of murine gammaherpesvirus 68 reactivates the complete lytic cycle from latency. Journal of Virology. 74, 3659-3667.[Open Access Full Text] [PDF]PDF
  • 1999

  • Husain, S.M., Usherwood, E.J., Dyson, H, Coleclough, C., Woodland, D.L., Blackman, M.A., Stewart, J.P. and Sample, J.T.  (1999). Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8+ T lymphocytes. Proceedings of the National Academy of Sciences, USA. 96, 7508-7513. [Open Access Full Text] [PDF]PDF
  • Dutia, B.M., Stewart, J.P., Clayton, R.A.E., Dyson, H. and Nash, A.A. (1999). Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus 68 in vitro. Journal of General Virology. 80, 2729-2736. [Open Access Full Text] [PDF]PDF
  • Stewart, J.P., Micali, N., Usherwood, E.J., Bonina, L., and Nash, A.A. (1999). A model system for gammaherpesvirus vaccination: murine gammaherpesvirus 68 glycoprotein 150 protects against virus-induced mononucleosis. Vaccine. 17, 152-157. [Full Text on Publisher Website] [PDF]PDF
  • 1998

  • Stewart, J.P., Usherwood, E.J., Ross, A., Dyson, H., and Nash, A.A. (1998). Lung epithelial cells are a major site of murine gammaherpesvirus persistence. Journal of Experimental Medicine. 187, 1941-1951. [Open Access Full Text] [PDF]PDF
  • 1997

  • Mackett, M., Stewart, J.P., Pepper, S., Chee, M., Efstathiou, S., Nash, A.A., and Arrand, J.R. (1997). Genetic content and preliminary transcriptional analysis of a representative region of murine gammaherpesvirus 68. Journal of General Virology. 78, 1425-1433. [Open Access PDF] [PDF]PDF
  • 1996

  • Pepper, S.deV., Stewart, J.P., Arrand, J.R., and Mackett, M. (1996). Murine gammaherpesvirus-68 encodes homologues of thymidine kinase and glycoprotein H: sequence, expression and characterization of pyrimidine kinase activity. Virology. 219, 475-479. [Full Text on Publisher Website] [PDF]PDF
  • Stewart, J.P., Janjua, N.J., Pepper, S.deV., Bennion, G., Mackett, M., Allen, T., Arrand, J.R., and Nash, A.A. (1996). Identification and characterization of murine gammaherpesvirus 68 (MHV-68) gp150: a virion membrane glycoprotein. Journal of Virology. 70, 3528-3535. [Open Access Full Text] [PDF]PDF
  • Usherwood, E.J., Stewart, J.P. and Nash, A.A. (1996). Characterization of tumor cell lines derived from murine gammaherpesvirus 68-infected mice. Journal of Virology. 70, 6516-6518. [Open Access Full Text] [PDF]PDF
  • Usherwood, E.J., Stewart, J.P., Robertson, K., Allen, D.J. and Nash, A.A. (1996). Absence of splenic latency in murine gammaherpesvirus 68-infected B-cell deficient mice. Journal of General Virology. 77, 2819-2825. [Full Text at Publisher Website] [PDF]PDF
  • 1994

  • Stewart, J.P., Janjua, N.J., Sunil-Chandra, N.P., Nash, A.A. and Arrand, J.R. (1994). Characterization of murine gammaherpesvirus 68 (MHV-68) glycoprotein B (gB) homolog - similarity to Epstein-Barr virus gB (gp110). Journal of Virology. 68. 6496-6504. [Open Access Full Text] [PDF]PDF

Posters

Posters relating to this work presented at international meetings have been submitted to Faculty of 1000 posters and can be found using the links below

The role of a chemokine binding protein encoded by MHV-68 in the pulmonary infection of its natural host  - presented at the 30th International Herpesvirus Workshop 2005, 30 Jul - 5 Aug 2005

Murid gammaherpesvirus infection in a natural host - presented at the 29th International Herpesvirus Workshop 2004, 25 - 30 Jul 2004