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Interferon-mediated development of influenza virus resistance in hybrids between Mx gene-bearing and control mouse
Abstract:
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.
Insights
The Mx gene product is induced by interferon (IFN) and directly interferes with orthomyxovirus replication, enhancing antiviral resistance in cells. This study clarifies the role of Mx in IFN-mediated defense against influenza viruses.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Interferon (IFN) confers antiviral resistance against orthomyxoviruses.
- The gene Mx is associated with enhanced IFN-mediated antiviral resistance.
- The precise role and induction of Mx by IFN were not fully understood.
Purpose of the Study:
- To investigate whether the gene Mx is induced by IFN.
- To determine if the Mx gene product acts independently or in concert with IFN.
- To elucidate the mechanism of Mx-mediated antiviral resistance against influenza viruses.
Main Methods:
- Formation of binucleate heterokaryons and cybrids from Mx-bearing and non-bearing cells.
- Fusion of cells with varying IFN treatment durations.
- Challenge with influenza virus and assessment of viral yield and resistance.
Main Results:
- Mx-bearing cells showed no constitutive antiviral activity without IFN treatment.
- Heterokaryons with IFN-treated Mx/Mx cells exhibited resistance characteristic of the Mx-containing cell.
- Resistance increased with IFN treatment duration in Mx/Mx cells, indicating IFN-mediated induction of Mx.
Conclusions:
- The product of the gene Mx is induced by IFN.
- Mx product directly or indirectly interferes with orthomyxovirus replication.
- Antiviral resistance is mediated by IFN-induced Mx gene expression, not cytoplasmic factors.