1887

Abstract

To better understand the role of the M2 protein of the murine herpes virus strain 68 (MHV-68) , B-lymphocyte-restricted, M2-transgenic mice were constructed. The transgenic mice contained normal B-cell subpopulations in bone marrow, lymph nodes and spleen. After immunization with sheep red blood cells, spleens from M2-transgenic mice had increased germinal centres. Transgenic mice responded to the T-cell-dependent antigen keyhole limpet haemocyanin (KLH) with higher levels of secondary IgM and IgG2a antibodies than WT mice. Normal and M2-transgenic mice were infected with WT and M2 frame-shift mutant (M2FS) MHV-68 viruses. The pathogenesis of M2-transgenic mice infected with the M2-deficient mutant virus did not revert to that observed upon infection of normal mice with WT virus. However, the higher reactivation levels late after M2-transgenic mice were infected with WT virus reflected the importance of M2 as a target for the immune response, and thus with an impact on the establishment of latency. Finally, there was markedly less apoptosis in B-cells from M2-transgenic mice infected with either WT or M2FS mutant than from similarly infected WT mice, consistent with the published inhibitory influence of M2 on apoptosis . Thus, M2 provides a strategy to increase the pool of germinal centre B-cells through inhibition of apoptosis in the infected cell.

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/content/journal/jgv/10.1099/vir.0.050013-0
2013-07-01
2024-04-16
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References

  1. Clambey E. T., Virgin H. W. IV, Speck S. H. 2002; Characterization of a spontaneous 9.5-kilobase-deletion mutant of murine gammaherpesvirus 68 reveals tissue-specific genetic requirements for latency. J Virol 76:6532–6544 [View Article][PubMed]
    [Google Scholar]
  2. Coutelier J. P., van der Logt J. T., Heessen F. W., Warnier G., Van Snick J. 1987; IgG2a restriction of murine antibodies elicited by viral infections. J Exp Med 165:64–69 [View Article][PubMed]
    [Google Scholar]
  3. Efstathiou S., Ho Y. M., Minson A. C. 1990; Cloning and molecular characterization of the murine herpesvirus 68 genome. J Gen Virol 71:1355–1364 [View Article][PubMed]
    [Google Scholar]
  4. Flaño E., Kim I.-J., Moore J., Woodland D. L., Blackman M. A. 2003; Differential gamma-herpesvirus distribution in distinct anatomical locations and cell subsets during persistent infection in mice. J Immunol 170:3828–3834[PubMed] [CrossRef]
    [Google Scholar]
  5. Herskowitz J. H., Jacoby M. A., Speck S. H. 2011; The murine gammaherpesvirus 68 M2 gene is required for efficient reactivation from latently infected B cells. J Virol 85 (6):3041 [View Article][PubMed]
    [Google Scholar]
  6. Husain, S. M., Usherwood, E. J., Dyson, H., Coleclough, C. & Coppola, M. A. Woodland, D. L., Blackman, M. A. Stewart, J. P. & Sample, J. T. (1999 Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8(+) T lymphocytes. Proc Natl Acad Sci U S A 96, 7508–7513
  7. Jacoby M. A., Virgin H. W. IV, Speck S. H. 2002; Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation. J Virol 76:1790–1801 [View Article][PubMed]
    [Google Scholar]
  8. Liang X., Collins C. M., Mendel J. B., Iwakoshi N. N., Speck S. H. 2009; Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5:e1000677 [View Article][PubMed]
    [Google Scholar]
  9. Macrae A. I., Dutia B. M., Milligan S., Brownstein D. G., Allen D. J., Mistrikova J., Davison A. J., Nash A. A., Stewart J. P. 2001; Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis. J Virol 75:5315–5327 [View Article][PubMed]
    [Google Scholar]
  10. Macrae A. I., Usherwood E. J., Husain S. M., Flaño E., Kim I.-J., Woodland D. L., Nash A. A., Blackman M. A., Sample J. T., Stewart J. P. 2003; Murid herpesvirus 4 strain 68 M2 protein is a B-cell-associated antigen important for latency but not lymphocytosis. J Virol 77:9700–9709 [View Article][PubMed]
    [Google Scholar]
  11. Madureira P. A., Matos P., Soeiro I., Dixon L. K., Simas J. P., Lam E. W. 2005; Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. J Biol Chem 280:37310–37318 [View Article][PubMed]
    [Google Scholar]
  12. Marques S., Alenquer M., Stevenson P. G., Simas J. P. 2008; A single CD8+ T cell epitope sets the long-term latent load of a murid herpesvirus. PLoS Pathog 4:e1000177 [View Article][PubMed]
    [Google Scholar]
  13. Pearce A. C., Senis Y. A., Billadeau D. D., Turner M., Watson S. P., Vigorito E. 2004; Vav1 and vav3 have critical but redundant roles in mediating platelet activation by collagen. J Biol Chem 279:53955–53962 [View Article][PubMed]
    [Google Scholar]
  14. Pires de Miranda M., Alenquer M., Marques S., Rodrigues L., Lopes F., Bustelo X. R., Simas J. P. 2008; The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly. PLoS ONE 3:e1654 [View Article][PubMed]
    [Google Scholar]
  15. Rodrigues L., Pires de Miranda M., Caloca M. J., Bustelo X. R., Simas J. P. 2006; Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol 80:6123–6135 [View Article][PubMed]
    [Google Scholar]
  16. Siegel A. M., Herskowitz J. H., Speck S. H. 2008; The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog 4:e1000039 [View Article][PubMed]
    [Google Scholar]
  17. Simas J. P., Marques S., Bridgeman A., Efstathiou S., Adler H. 2004; The M2 gene product of murine gammaherpesvirus 68 is required for efficient colonization of splenic follicles but is not necessary for expansion of latently infected germinal centre B cells. J Gen Virol 85:2789–2797 [View Article][PubMed]
    [Google Scholar]
  18. Thorley-Lawson D. A. 2001; Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1:75–82 [View Article][PubMed]
    [Google Scholar]
  19. Thorley-Lawson D. A., Babcock G. J. 1999; A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. Life Sci 65:1433–1453 [View Article][PubMed]
    [Google Scholar]
  20. Willer D. O., Speck S. H. 2003; Long-term latent murine Gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo. J Virol 77:8310–8321 [View Article][PubMed]
    [Google Scholar]
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