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Journal of Virology, September 2003, p. 9960-9968, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9960-9968.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus Interleukin-18-Binding Protein Promotes Virulence by Reducing Gamma Interferon Production and Natural Killer and T-Cell Activity

Patrick C. Reading{dagger} and Geoffrey L. Smith*

Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, London W2 1PG, United Kingdom

Received 14 April 2003/ Accepted 19 June 2003

Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes natural killer (NK) and T-cell activation. Several poxviruses, including vaccinia virus (VV), encode a soluble IL-18-binding protein (IL-18bp). The role of the VV IL-18bp (gene C12L) in vivo was studied with wild-type (vC12L), deletion mutant (v{Delta}C12L), and revertant (vC12L-rev) viruses in a murine intranasal model of infection. The data show that v{Delta}C12L was markedly attenuated, characterized by a mild weight loss and reduced virus titers in lungs, brain, and spleen. Three days after infection, NK cytotoxic activity was augmented in the lung, spleen, and mediastinal lymph nodes (MLNs) of v{Delta}C12L-infected mice compared to controls. Seven days after infection, v{Delta}C12L-infected mice displayed heightened VV-specific cytotoxic T-lymphocyte (CTL) responses in the lungs, spleen, and MLNs. Gamma interferon (IFN-{gamma}) levels were also dramatically elevated in lavage fluids and cells from lungs of mice infected with v{Delta}C12L. Finally, we demonstrate that IL-18 is produced in vitro and in vivo after VV infection. Taken together, these data demonstrate a role for the vIL-18bp in counteracting IL-18 in both the innate and the specific immune response to VV infection and indicate that the ability of IL-18 to promote vigorous T-cell responses (cytotoxic activity and IFN-{gamma} production) is a critical factor in the accelerated clearance of the v{Delta}C12L mutant.

* Corresponding author. Mailing address: Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44-207-594-3972. Fax: 44-207-594-3973. E-mail: glsmith{at}ic.ac.uk.

{dagger} Present address: Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.

Journal of Virology, September 2003, p. 9960-9968, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9960-9968.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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