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Interferon-mediated Development of Influenza Virus Resistance in Hybrids between Mx Gene-bearing and Control Mouse Embryo Fibroblasts

Michael Ruff

Institute for Immunology and Virology, University of Zurich, 8028 Zurich, Switzerland

The presence of the gene Mx results in a greater interferon (IFN)-mediated antiviral resistance in cells challenged by orthomyxovirus. In the absence of IFN no difference in influenza virus yield was detected in Mx-bearing (Mx/Mx) or non-bearing (+/+) mouse embryo fibroblasts. Although the putative product of the gene Mx has been suggested to act in concert with IFN it is not clear whether Mx was itself induced by IFN. Binucleate heterokaryons were formed by the fusion of an Mx/Mx cell and an IFN-treated +/+ cell. Results show that no constitutive activity was present in the Mx cell that was not IFN-treated, which was capable of enhancing the marginal anti-influenza virus resistance characteristic of the IFN-treated +/+ cell. Heterokaryons between +/+ cells and IFN-treated Mx/Mx cells, however, showed resistance characteristic of the Mx-containing cell. Hybrids of fusions between IFN-pretreated +/+ cells and Mx/Mx cells that had been IFN-treated for 1 to 2 h revealed a graded response to influenza virus growth inhibition. Resistance in such hybrids increased commensurate with the development of the anti-influenza virus state in the Mx/Mx donor. No synergistic enhancement of influenza virus growth inhibition was observed. These data suggest that the product of the gene Mx is induced by IFN. Cybrids, constructed between nucleated +/+ or Mx/Mx cells and enucleated Mx/Mx cytoplasts, when subsequently treated with IFN and challenged with influenza virus, showed resistance characteristic only of the nucleated cell donor. Thus, no cytoplasmic component present in Mx-bearing cytoplasts is able to cooperate with the nuclear elements of a +/+ cell to induce a state of high influenza virus resistance. The simplest interpretation of these data is that specific resistance is not the result of modifications of virus growth or IFN activities but probably occurs by the IFN-mediated induction of the gene Mx, the product of which directly, or indirectly, interferes with orthomyxovirus replication.

Keywords: interferon, influenza virus, Mx gene, resistance to infection, heterokaryons

Present address: Laboratory of Molecular Biology, Building 37, Room 4B27, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205, U.S.A.

Received 20 July 1982; accepted 10 January 1982.