title: The viral nucleoprotein determines Mx sensitivity of influenza A viruses.
abstract: Host restriction factors play a crucial role in preventing trans-species transmission of viral pathogens. In mammals, the interferon-induced Mx GTPases are powerful antiviral proteins restricting orthomyxoviruses. Hence, the human MxA GTPase may function as an efficient barrier against zoonotic introduction of influenza A viruses into the human population. Successful viruses are likely to acquire adaptive mutations allowing them to evade MxA restriction. We compared the 2009 pandemic influenza A virus [strain A/Hamburg/4/09 (pH1N1)] with a highly pathogenic avian H5N1 isolate [strain A/Thailand/1(KAN-1)/04] for their relative sensitivities to human MxA and murine Mx1. The H5N1 virus was highly sensitive to both Mx GTPases, whereas the pandemic H1N1 virus was almost insensitive. Substitutions of the viral polymerase subunits or the nucleoprotein (NP) in a polymerase reconstitution assay demonstrated that NP was the main determinant of Mx sensitivity. The NP of H5N1 conferred Mx sensitivity to the pandemic H1N1 polymerase, whereas the NP of pandemic H1N1 rendered the H5N1 polymerase insensitive. Reassortant viruses which expressed the NP of H5N1 in a pH1N1 genetic background and vice versa were generated. Congenic Mx1-positive mice survived intranasal infection with these reassortants if the challenge virus contained the avian NP. In contrast, they succumbed to infection if the NP of pH1N1 origin was present. These findings clearly indicate that the origin of NP determines Mx sensitivity and that human influenza viruses acquired adaptive mutations to evade MxA restriction. This also explains our previous observations that human and avian influenza A viruses differ in their sensitivities to Mx.
authors.affiliation: Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany. georg.kochs@uniklinik-freiburg.de
authors.forename: Petra
authors.initials: P
authors.lastname: Zimmermann
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mänz
authors.forename: Otto
authors.initials: O
authors.lastname: Haller
authors.forename: Martin
authors.initials: M
authors.lastname: Schwemmle
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
mesh_terms: D000818:Animals; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000502:physiology*; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D064547:Myxovirus Resistance Proteins; D041681:NIH 3T3 Cells; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016865:Reassortant Viruses / Q000235:genetics / Q000502:physiology; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: C579071:MX1 protein, human; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases; D019204:GTP-Binding Proteins