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Title

The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA.

Authors
Riegger, David
Hai, Rong
Dornfeld, Dominik
Mänz, Benjamin
Leyva-Grado, Victor
Sánchez-Aparicio, Maria T
Albrecht, Randy A
Palese, Peter
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Published in Journal of Virology. 2015, vol. 89, no. 4, p. 2241-2252
Abstract Interferon-induced Mx proteins show strong antiviral activity against influenza A viruses (IAVs). We recently demonstrated that the viral nucleoprotein (NP) determines resistance of seasonal and pandemic human influenza viruses to Mx, while avian isolates retain Mx sensitivity. We identified a surface-exposed cluster of amino acids in NP of pandemic A/BM/1/1918 (H1N1), comprising isoleucine-100, proline-283, and tyrosine-313, that is essential for reduced Mx sensitivity in cell culture and in vivo. This cluster has been maintained in all descendant seasonal strains, including A/PR/8/34 (PR/8). Accordingly, two substitutions in the NP of PR/8 [PR/8(mut)] to the Mx-sensitive amino acids (P283L and Y313F) led to attenuation in Mx1-positive mice. Serial lung passages of PR/8(mut) in Mx1 mice resulted in a single exchange of tyrosine to asparagine at position 52 in NP (in close proximity to the amino acid cluster at positions 100, 283, and 313), which partially compensates loss of Mx resistance in PR/8(mut). Intriguingly, the NP of the newly emerged avian-origin H7N9 virus also contains an asparagine at position 52 and shows reduced Mx sensitivity. N52Y substitution in NP results in increased sensitivity of the H7N9 virus to human Mx, indicating that this residue is a determinant of Mx resistance in mammals. Our data strengthen the hypothesis that the human Mx protein represents a potent barrier against zoonotic transmission of avian influenza viruses. However, the H7N9 viruses overcome this restriction by harboring an NP that is less sensitive to Mx-mediated host defense. This might contribute to zoonotic transmission of H7N9 and to the severe to fatal outcome of H7N9 infections in humans.
Keywords AnimalsBirdsCell LineChinaHumansImmune EvasionInfluenza A Virus, H7N9 Subtype/growth & development/immunologyInfluenza in Birds/virologyInfluenza, Human/immunologyMice, Inbred C57BLMolecular Sequence DataMyxovirus Resistance Proteins/immunologyRNA, Viral/geneticsRNA-Binding Proteins/genetics/immunologySequence Analysis, DNAViral Core Proteins/genetics/immunologyZoonoses/transmission/virology
Identifiers
PMID: 25505067
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Article (Published version) (2.4 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Research group Intéractions entre les pathogènes viraux et bactériens (947)
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RIEGGER, David et al. The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. In: Journal of Virology, 2015, vol. 89, n° 4, p. 2241-2252. https://archive-ouverte.unige.ch/unige:76386

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Deposited on : 2015-10-22

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