Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein

PLoS Pathog. 2013 Mar;9(3):e1003279. doi: 10.1371/journal.ppat.1003279. Epub 2013 Mar 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Resistance / genetics
  • Evolution, Molecular
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics*
  • Humans
  • Immune Evasion / genetics*
  • Influenza A Virus, H1N1 Subtype / genetics*
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Mice
  • Mice, Inbred BALB C
  • Mutation*
  • Myxovirus Resistance Proteins
  • Nucleoproteins / genetics*
  • Orthomyxoviridae Infections / genetics*
  • Orthomyxoviridae Infections / immunology
  • Pandemics
  • Protein Structure, Secondary
  • Selection, Genetic
  • Zoonoses / virology


  • MX1 protein, human
  • Mx1 protein, mouse
  • Myxovirus Resistance Proteins
  • Nucleoproteins
  • GTP-Binding Proteins

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft, grant Ko 1579/8-1 to GK and the Bundesministerium für Bildung und Forschung (FluResearchNet) to MS and RZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.