Expression of Mouse Interleukin-4 by a Recombinant Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and Overcomes Genetic Resistance to Mousepox

February 2001
J. Virology 75, 1205-1210

Ronald J. Jackson,1,2,* Alistair J. Ramsay,2, Carina D. Christensen,2 Sandra Beaton,1 Diana F. Hall,1, and Ian A. Ramshaw2 Pest Animal Control Cooperative Research Centre, CSIRO Sustainable Ecosystems,1 and Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University,2 Canberra, Australia

• Original goal was to use mousepox as a vector to immunize rodents against a protein on their eggs and render them infertile; inclusion of IL-4 gene in the vector was expected to enhance the antibody response to the egg proteins.

• Recombinant mousepox-IL-4 virus suppressed normal anti-viral cell-mediated immune responses (NK and CTL cells) needed to control the infection.

• Consequently, the recombinant virus was highly virulent and killed mice that were normally genetically resistant to mousepox and, importantly, also killed a substantial portion of mice that were immunized against mousepox.

Were the authors surprised by the enhanced pathogenicity?
Not entirely.

They noted:

• CTL activity is important for clearance of virus infections; over-expression or systemic expression of IL-4 impedes the development of CTL activity.

• The neutralization of any one of the major cell-mediated anti-viral activities, including CTL activity, had previously been shown to result in fulminant mousepox disease in otherwise resistant mice.

• IL-4 had been expressed from another poxvirus, vaccinia virus, which is much less pathogenic in the mouse than mousepox. Infected mice cleared the recombinant virus more slowly than they cleared normal vaccinia virus.

J. Virology 75, 8353-8355, September 2001

Creation of Killer Poxvirus Could Have Been Predicted

Arno Müllbacher* and Mario Lobigs
Division of Immunology and Cell Biology, John Curtin School of Medical Research,
The Australian National University, Canberra City, Australian Capital Territory 2601, Australia

A conundrum illustrated by this case:

Assuming that it would be desirable to limit access to certain types of information, where do we draw the line?

• Discovery of the function of IL-4?

• Elucidation of IL-4 effects in a vaccinia model?

• Demonstration that IL-4 can make a mouse virus more pathogenic?

http://www.csis.org/tech/ssi/sonsw/s_shenk.pdf