64 : Transgenic mice carrying interferon-regulated human MxA locus are highly resistant to avian but not human influenza A viruses
Mx proteins are interferon (IFN)-induced GTPases that confer antiviral activity in many vertebrates. Mouse Mx1 accumulates in the nucleus of IFN-treated cells and mediates antiviral activity in vitro and in vivo against orthomyxoviruses, such as influenza A and Thogoto viruses. Human MxA is a cytoplasmic protein that exhibits an even broader antiviral activity in cultured cells. However, to date, its in vivo potential remained poorly investigated. To fill this knowledge gap, we created a new mouse line that carries the entire human Mx locus as a transgene. We found that high levels of MxA were induced in cultured embryonic fibroblasts from transgenic mice upon treatment with IFN-α. Further, high levels of MxA were found in most organs of transgenic mice at 24 h post treatment with recombinant IFN-α but not in organs of untreated animals, indicating faithful regulation of the human Mx locus in our transgenic mouse. Challenge experiments demonstrated that our transgenic mice are well protected from lethal infections with Thogoto virus and highly pathogenic avian influenza A virus strains. Interestingly, protection against influenza A virus strains of human origin, such as the H1N1 strains A/PR/8/34 and A/WSN/33 or the H3N2 strain A/HK/68, was only moderate. Our results provide strong indirect evidence that the Mx locus plays an important role in influenza A virus protection of humans. They further suggest that circulating human influenza virus strains have acquired adaptive mutations which permit viral replication in the presence of Mx.