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

Benjamin Mänz; Dominik Dornfeld; Veronika Götz; Roland Zell; Petra Zimmermann; Otto Haller; Georg Kochs; Martin Schwemmle

doi:10.1371/journal.ppat.1003279

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.

Authors

Benjamin Mänz¹, Dominik Dornfeld, Veronika Götz, Roland Zell, Petra Zimmermann, Otto Haller, Georg Kochs, Martin Schwemmle

Affiliation

¹ Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany.

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.

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

Substances

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

Grants and funding

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.