title: In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein.
abstract: Zoonotic transmission of influenza A viruses can give rise to devastating pandemics, but currently it is impossible to predict the pandemic potential of circulating avian influenza viruses. Here, we describe a new mouse model suitable for such risk assessment, based on the observation that the innate restriction factor MxA represents an effective species barrier that must be overcome by zoonotic viruses. Our mouse lacks functional endogenousMxgenes but instead carries the humanMX1locus as a transgene. Such 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 nontransgenic littermates. Influenza A viruses that successfully established stable lineages in humans have acquired adaptive mutations which allow partial MxA escape. Accordingly, 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 parental virus, demonstrating that a few amino acid changes in the viral target protein can mediate escape from MxA restriction in vivo. Similar mutations probably need to be acquired by emerging influenza A viruses before they can spread in the human population.
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Christoph M
authors.identifier: 0000-0002-4459-9372
authors.initials: CM
authors.lastname: Deeg
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.|Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, 79085 Freiburg, Germany.|Microbiology Department, Faculty of Science, Ain Shams University, 11566 Cairo, Egypt.
authors.forename: Ebrahim
authors.identifier: 0000-0001-7870-9755
authors.initials: E
authors.lastname: Hassan
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Pascal
authors.identifier: 0000-0002-0430-2095
authors.initials: P
authors.lastname: Mutz
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Lara
authors.identifier: 0000-0002-4314-0172
authors.initials: L
authors.lastname: Rheinemann
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Veronika
authors.identifier: 0000-0003-3223-8745
authors.initials: V
authors.lastname: Götz
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Magar
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schilling
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kallfass
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.|Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, 79085 Freiburg, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Nürnberger
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Soubies
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Otto
authors.identifier: 0000-0003-1202-0909
authors.initials: O
authors.lastname: Haller
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwemmle
authors.affiliation: Institute of Virology, Medical Center University of Freiburg, 79106 Freiburg, Germany peter.staeheli@uniklinik-freiburg.de.
authors.forename: Peter
authors.identifier: 0000-0001-7057-6177
authors.initials: P
authors.lastname: Staeheli
mesh_terms: D000818:Animals; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D053126:Influenza A Virus, H7N7 Subtype / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000276:immunology*; D009698:Nucleoproteins / Q000235:genetics*
chemical_list: C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009698:Nucleoproteins