MxA represents a decisive species barrier against influenza viruses in vivo Abstract: In vivo evasion of MxA reveals pandemic potential of emerging influenza A viruses<br><br>Christoph M. Deeg1 $ Ebrahim Hassan1 2 3 $ Pascal Mutz1 $ Lara Rheinemann1 Veronika Götz1 Linda Magar1 Mirjam Schilling1 Carsten Kallfass1 Cindy Nürnberger1 2 Sébastien Soubies1 Georg Kochs1 Otto Haller1 Martin Schwemmle1 and Peter Staeheli1<br><br>1 Institute of Virology Medical Center University of Freiburg Freiburg Germany<br>2 Spemann Graduate School of Biology and Medicine (SGBM) University of Freiburg <br>3 Microbiology Department Faculty of Science Ain Shams University Cairo Egypt <br>$ These authors contributed equally to this work<br><br>Influenza A viruses pose a constant threat to humans because zoonotic viral transmissions can cause severe disease and give rise to devastating pandemics. Currently it is not possible to predict the pandemic potential of avian influenza A viruses. We now describe a new mouse model suitable for risk assessment. It is based on the finding that innate restriction factors represent effective species barriers that need to be overcome by viruses trying to invade a human host. In mice innate immune control of influenza viruses is mediated by the interferon regulated Mx1 gene. The MX1 orthologue of humans (encoding MxA protein) provides broad resistance to influenza and other viruses in cell culture systems. MxA is targeting the nucleoprotein of influenza A viruses which encapsidates the viral genome and is pivotal to virus replication. Influenza A viruses that successfully established stable lineages in humans acquired adaptive mutations in the nucleoprotein that allow partial MxA escape in cell culture experiments. Our new mouse strain lacks functional endogenous Mx genes but instead carries the human MX1 locus as transgene. Our transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses but were almost as susceptible to infection with influenza viruses of human origin as non transgenic littermates. We further demonstrate that an engineered avian H7N7 influenza virus carrying a nucleoprotein with signature mutations typically found in human virus isolates was more virulent in transgenic mice than the parental virus. These findings illustrate that a few amino acid changes in the viral nucleoprotein can mediate escape from MxA restriction in vivo. They further suggest that equivalent mutations need to be acquired by any emerging influenza A viruses before the ...