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A New Influenza Virus Virulence Determinant: The NS1 Protein Four C-Terminal Residues Modulate Pathogenicity

The virulence of influenza virus is a multigenic trait. One determinant of virulence is the multifunctional NS1 protein that functions in several ways to defeat the cellular innate immune response. Recent large-scale genome sequence analysis of avian influenza virus isolates indicated that four C-te...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (11), p.4381-4386
Main Authors: Jackson, David, Hossain, Md. Jaber, Hickman, Danielle, Perez, Daniel R., Lamb, Robert A.
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description The virulence of influenza virus is a multigenic trait. One determinant of virulence is the multifunctional NS1 protein that functions in several ways to defeat the cellular innate immune response. Recent large-scale genome sequence analysis of avian influenza virus isolates indicated that four C-terminal residues of the NS1 protein is a PDZ ligand domain of the X-S/T-X-V type and it was speculated that it may represent a virulence determinant. To test this hypothesis, by using mice as a model system, the four C-terminal amino acid residues of a number of influenza virus strains were engineered into the A/WSN/33 virus NS1 protein by reverse genetics and the pathogenicity of the viruses determined. Viruses containing NS1 sequences from the 1918 H1N1 and H5N1 highly pathogenic avian influenza (HPAI) viruses demonstrated increased virulence in infected mice compared with wt A/WSN/33 virus, as characterized by rapid loss of body weight, decreased survival time, and decreased mean lethal dose. Histopathological analysis of infected mouse lung tissues demonstrated severe alveolitis, hemorrhaging, and spread of the virus throughout the entire lung. The increase in pathogenicity was not caused by the overproduction of IFN, suggesting the NS1 protein C terminus may interact with PDZ-binding protein(s) and modulate pathogenicity through alternative mechanisms.
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subjects Amino Acid Sequence
Amino acids
Animals
Avian influenza virus
Binding sites
Biological Sciences
Cell Line
Cells
Disease Models, Animal
Dogs
Female
Genetic mutation
H1N1 subtype influenza A virus
H5N1 subtype influenza A virus
Humans
Influenza
Influenza A virus
Influenza A Virus, H1N1 Subtype - chemistry
Influenza A Virus, H1N1 Subtype - genetics
Influenza A Virus, H1N1 Subtype - metabolism
Influenza A Virus, H1N1 Subtype - pathogenicity
Influenza A Virus, H5N1 Subtype - chemistry
Influenza A Virus, H5N1 Subtype - genetics
Influenza A Virus, H5N1 Subtype - metabolism
Influenza A Virus, H5N1 Subtype - pathogenicity
Influenza virus
Interferons - biosynthesis
Lung Diseases - metabolism
Lung Diseases - pathology
Lungs
Mice
Mice, Inbred BALB C
Microbiology
Molecular Sequence Data
Mutation - genetics
Orthomyxoviridae
Pathogens
Proteins
Recombination, Genetic - genetics
Rodents
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Virulence
Virulence Factors - chemistry
Virulence Factors - genetics
Virulence Factors - metabolism
Viruses
title A New Influenza Virus Virulence Determinant: The NS1 Protein Four C-Terminal Residues Modulate Pathogenicity
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