[en] The vaccinia virus (VACV) N1 protein is an intracellular virulence factor that has a Bcl-2-like structure and inhibits both apoptosis and signalling from the interleukin 1 receptor, leading to nuclear factor kappa B activation. Here, we investigated the immune response to intranasal infection with a virus lacking the N1L gene (vDeltaN1L) compared with control viruses expressing N1L. Data presented show that deletion of N1L did not affect the proportion of CD4+ and CD8+ T cells infiltrating the lungs or the cytotoxic T-cell activity of these cells. However, vDeltaN1L induced an increased local natural killer cell activity between days 4 and 6 post-infection. In addition, in the absence of N1 the host inflammatory infiltrate was characterized by a reduced proportion of lymphocytes bearing the early activation marker CD69. Notably, there was a good correlation between the level of CD69 expression and weight loss. The implications of these findings are discussed.
Disciplines :
Immunology & infectious disease
Author, co-author :
Jacobs, Nathalie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Bartlett, Nathan W
Clark, Richard H
Smith, Geoffrey L; Imperial College London
Language :
English
Title :
Vaccinia virus lacking the Bcl-2-like protein N1 induces a stronger natural killer cell response to infection.
Publication date :
2008
Journal title :
Journal of General Virology
ISSN :
0022-1317
eISSN :
1465-2099
Publisher :
Society for General Microbiology, London, United Kingdom
Antoine, G., Scheiflinger, F., Dorner, F. & Falkner, F. G. (1998). The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses. Virology 244, 365-396.
Aoyagi, M., Zhai, D., Jin, C., Aleshin, A. E., Stec, B., Reed, J. C. & Liddington, R. C. (2007). Vaccinia virus N1L protein resembles a B cell lymphoma-2 (Bcl-2) family protein. Protein Sci 16, 118-124.
Bartlett, N., Symons, J. A., Tscharke, D. C. & Smith, G. L. (2002). The vaccinia virus N1L protein is an intracellular homodimer that promotes virulence. J Gen Virol 83, 1965-1976.
Bellows, D. S., Chau, B. N., Lee, P., Lazebnik, Y., Burns, W. H. & Hardwick, J. M. (2000). Antiapoptotic herpesvirus Bcl-2 homologs escape caspase-mediated conversion to proapoptotic proteins. J Virol 74, 5024-5031.
Billings, B., Smith, S. A., Zhang, Z., Lahiri, D. K. & Kotwal, G. J. (2004). Lack of N1L gene expression results in a significant decrease of vaccinia virus replication in mouse brain. Ann N Y Acad Sci 1030, 297-302.
Chen, R. A., Ryzhakov, G., Cooray, S., Randow, F. & Smith, G. L. (2008). Inhibition of IκB kinase by vaccinia virus virulence factor B14. PLoS Pathog 4, e22.
Clark, R. H., Kenyon, J. C., Bartlett, N. W., Tscharke, D. C. & Smith, G. L. (2006). Deletion of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy. J Gen Virol 87, 29-38.
Cooray, S., Bahar, M. W., Abrescia, N. G., McVey, C. E., Bartlett, N. W., Chen, R. A., Stuart, D. I., Grimes, J. M. & Smith, G. L. (2007). Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein. J Gen Virol 88, 1656-1666.
de Lima, B. D., May, J. S., Marques, S., Simas, J. P. & Stevenson, P. G. (2005). Murine gammaherpesvirus 68 bcl-2 homologue contributes to latency establishment in vivo. J Gen Virol 86, 31-40.
DiPerna, G., Stack, J., Bowie, A. G., Boyd, A., Kotwal, G., Zhang, Z., Arvikar, S., Latz, E., Fitzgerald, K. A. & Marshall, W. L. (2004). Poxvirus protein N1L targets the I-κB kinase complex, inhibits signaling to NF-κB by the tumor necrosis factor superfamily of receptors, and inhibits NF-κB and IRF3 signaling by toll-like receptors. J Biol Chem 279, 36570-36578.
Esplugues, E., Sancho, D., Vega-Ramos, J., Martinez, C., Syrbe, U., Hamann, A., Engel, P., Sanchez-Madrid, F. & Lauzurica, P. (2003). Enhanced antitumor immunity in mice deficient in CD69. J Exp Med 197, 1093-1106.
Esplugues, E., Vega-Ramos, J., Cartoixa, D., Vazquez, B. N., Salaet, I., Engel, P. & Lauzurica, P. (2005). Induction of tumor NK-cell immunity by anti-CD69 antibody therapy. Blood 105, 4399-4406.
Foerster, M., Haefner, D. & Kroegel, C. (2002). Bcl-2-mediated regulation of CD69-induced apoptosis of human eosinophils: identification and characterization of a novel receptor-induced mechanism and relationship to CD95-transduced signalling. Scand J Immunol 56, 417-428.
Graham, S. C., Bahar, M. W., Cooray, S., Chen, R. A.-J., Whalen, D. W., Abrescia, N. G. A., Alderton, D., Owens, R. J., Stuart, D. I., Smith, G. L. & Grimes, J. M. (2008). Vaccinia virus proteins A52 and B14 share a Bcl-2-like fold but have evolved to inhibit NF-κB rather than apoptosis. PLoS Pathog 4, e1000128.
Hussell, T. & Openshaw, P. J. (1998). Intracellular IFN-γ expression in natural killer cells precedes lung CD8+ T cell recruitment during respiratory syncytial virus infection. J Gen Virol 79, 2593-2601.
Jacobs, N., Chen, R. A., Gubser, C., Najarro, P. & Smith, G. L. (2006). Intradermal immune response after infection with vaccinia virus. J Gen Virol 87, 1157-1161.
Jewett, A., Cacalano, N. A., Teruel, A., Romero, M., Rashedi, M., Wang, M. & Nakamura, H. (2006). Inhibition of nuclear factor kappa B (NFκB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation. Cancer Immunol Immunother 55, 1052-1063.
Kotwal, G. J., Hugin, A. W. & Moss, B. (1989). Mapping and insertional mutagenesis of a vaccinia virus gene encoding a 13,800-Da secreted protein. Virology 171, 579-587.
Krug, L. T., Moser, J. M., Dickerson, S. M. & Speck, S. H. (2007). Inhibition of NF-κB activation in vivo impairs establishment of gammaherpesvirus latency. PLoS Pathog 3, e11.
Ku, B., Woo, J. S., Liang, C., Lee, K. H., Hong, H. S., E., X., Kim, K. S., Jung, J. U. & Oh, B. H. (2008). Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral Bcl-2 of murine gamma-herpesvirus 68. PLoS Pathog 4, e25.
Kvansakul, M., van Delft, M. F., Lee, E. F., Gulbis, J. M., Fairlie, W. D., Huang, D. C. & Colman, P. M. (2007). A structural viral mimic of prosurvival Bcl-2: a pivotal role for sequestering proapoptotic Bax and Bak. Mol Cell 25, 933-942.
Moss, B. (2007). Poxviridae: the viruses and their replication. In Fields Virology, 5th edn, pp. 2905-2946. Edited by D. M. Knipe. Philadelphia: Lippincott Williams & Wilkins.
Opgenorth, A., Graham, K., Nation, N., Strayer, D. & McFadden, G. (1992). Deletion analysis of two tandemly arranged virulence genes in myxoma virus, M11L and myxoma growth factor. J Virol 66, 4720-4731.
Reading, P. C., Symons, J. A. & Smith, G. L. (2003). A soluble chemokine-binding protein from vaccinia virus reduces virus virulence and the inflammatory response to infection. J Immunol 170, 1435-1442.
Sancho, D., Gomez, M. & Sanchez-Madrid, F. (2005). CD69 is an immunoregulatory molecule induced following activation. Trends Immunol 26, 136-140.
Smith, G. L. (2007). Genus Orthopoxvirus: Vaccinia virus. In Poxviruses, pp. 1-45. Edited by A. A. Mercer, A. Schmidt & O. Weber. Berlin: Birkhauser-Verlag.
Tscharke, D. C. & Smith, G. L. (1999). A model for vaccinia virus pathogenesis and immunity based on intradermal injection of mouse ear pinnae. J Gen Virol 80, 2751-2755.
Wang, G. H., Garvey, T. L. & Cohen, J. I. (1999). The murine gammaherpesvirus-68 M11 protein inhibits Fas- and TNF-induced apoptosis. J Gen Virol 80, 2737-2740.
Zhang, Z., Abrahams, M. R., Hunt, L. A., Suttles, J., Marshall, W., Lahiri, D. K. & Kotwal, G. J. (2005). The vaccinia virus N1L protein influences cytokine secretion in vitro after infection. Ann N Y Acad Sci 1056, 69-86.
