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Journal of Virology, April 2007, p. 3346-3353, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01927-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection{triangledown}

Isaac G. Sakala,1 Geeta Chaudhri,1 R. Mark Buller,2 Anthony A. Nuara,2 Hongdong Bai,2 Nanhai Chen,2 and Gunasegaran Karupiah1*

Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia,1 Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, Saint Louis, Missouri 631042

Received 4 September 2006/ Accepted 2 January 2007

Ectromelia virus (ECTV), a natural mouse pathogen and the causative agent of mousepox, is closely related to variola virus (VARV), which causes smallpox in humans. Mousepox is an excellent surrogate small-animal model for smallpox. Both ECTV and VARV encode a multitude of host response modifiers that target components of the immune system and that are thought to contribute to the high mortality rates associated with infection. Like VARV, ECTV encodes a protein homologous to the ectodomain of the host gamma interferon (IFN-{gamma}) receptor 1. We generated an IFN-{gamma} binding protein (IFN-{gamma}bp) deletion mutant of ECTV to study the role of viral IFN-{gamma}bp (vIFN-{gamma}bp) in host-virus interaction and also to elucidate the contribution of this molecule to the outcome of infection. Our data show that the absence of vIFN-{gamma}bp does not affect virus replication per se but does have a profound effect on virus replication and pathogenesis in mice. BALB/c mice, which are normally susceptible to infection with ECTV, were able to control replication of the mutant virus and survive infection. Absence of vIFN-{gamma}bp from ECTV allowed the generation of an effective host immune response that was otherwise diminished by this viral protein. Mice infected with a vIFN-{gamma}bp deletion mutant virus, designated ECTV-IFN-{gamma}bp{Delta}, produced increased levels of IFN-{gamma} and generated robust cell-mediated and antibody responses. Using several strains of mice that exhibit differential degrees of resistance to mousepox, we show that recovery or death from ECTV infection is determined by a balance between the host's ability to produce IFN-{gamma} and the virus' ability to dampen its effects.

* Corresponding author. Mailing address: The John Curtin School of Medical Research, Australian National University, Acton, ACT 0200 Australia. Phone: 61-2-6125-4562. Fax: 61-2-6125-2595. E-mail: Guna.Karupiah{at}anu.edu.au.

{triangledown} Published ahead of print on 17 January 2007.

Journal of Virology, April 2007, p. 3346-3353, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01927-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, Y., Chaudhri, G., Jackson, R. J., Karupiah, G. (2009). IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection. J. Immunol. 183: 3324-3331 [Abstract] [Full Text]  
  • Xu, R.-H., Cohen, M., Tang, Y., Lazear, E., Whitbeck, J. C., Eisenberg, R. J., Cohen, G. H., Sigal, L. J. (2008). The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination. JEM 205: 981-992 [Abstract] [Full Text]  
  • Nuara, A. A., Walter, L. J., Logsdon, N. J., Yoon, S. I., Jones, B. C., Schriewer, J. M., Buller, R. M., Walter, M. R. (2008). Structure and mechanism of IFN-{gamma} antagonism by an orthopoxvirus IFN-{gamma}-binding protein. Proc. Natl. Acad. Sci. USA 105: 1861-1866 [Abstract] [Full Text]  


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