title: Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.
abstract: The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.
authors.affiliation: Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mänz
authors.forename: Dominik
authors.initials: D
authors.lastname: Dornfeld
authors.forename: Veronika
authors.initials: V
authors.lastname: Götz
authors.forename: Roland
authors.initials: R
authors.lastname: Zell
authors.forename: Petra
authors.initials: P
authors.lastname: Zimmermann
authors.forename: Otto
authors.initials: O
authors.lastname: Haller
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.forename: Martin
authors.initials: M
authors.lastname: Schwemmle
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D064547:Myxovirus Resistance Proteins; D009698:Nucleoproteins / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000276:immunology; D058873:Pandemics; D017433:Protein Structure, Secondary; D012641:Selection, Genetic; D015047:Zoonoses / Q000821:virology
chemical_list: C579071:MX1 protein, human; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D009698:Nucleoproteins; D019204:GTP-Binding Proteins
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