tetano
Editor, Senior Moderator
J Virol. 2016 Dec 21. pii: JVI.01930-16. doi: 10.1128/JVI.01930-16. [Epub ahead of print]
[h=1]NS1 protein amino acid changes D189N and V194I affect interferon responses, thermosensitivity and virulence of circulating H3N2 human influenza A viruses.[/h] Nogales A[SUP]1[/SUP], Martinez-Sobrido L[SUP]1[/SUP], Topham DJ[SUP]2,[/SUP][SUP]1[/SUP], DeDiego ML[SUP]2,[/SUP][SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza NS1 protein is a non-structural, multifunctional protein that counteracts host innate immune responses, modulating virus pathogenesis. NS1 protein variability in subjects infected with H3N2 IAVs during the 2010/2011 season was analyzed, finding amino acid changes in residues 86, 189, and 194. The consequences of these mutations in the NS1-mediated inhibition of IFN responses, and the pathogenesis of the virus were evaluated, showing that NS1 mutations D189N, and V194I impaired the ability of the NS1 protein to inhibit general gene expression, most probably because these mutations decreased the binding of NS1 to the cleavage and polyadenylation specificity factor 30 (CPSF30). A recombinant A/Puerto Rico/8/34 (PR8) H1N1 virus encoding the H3N2 NS1-D189N protein was slightly attenuated, whereas the virus encoding the H3N2 V194I NS1 protein was further attenuated in mice. The higher attenuation of this virus could not be explained by differences in the ability of the two NS1 proteins to counteract host innate immune responses, indicating that another factor must be responsible. In fact, we showed that the virus encoding the H3N2 V194I NS1 protein demonstrated a temperature-sensitive (ts) phenotype, providing a most likely explanation for the stronger attenuation observed. As far as we know, this is the first time describing that a mutation in NS1 residue 194 confers a ts phenotype. These studies are relevant in order to identify new residues important for NS1 functions, and in human influenza virus surveillance to assess mutations affecting the pathogenicity of circulating viruses.
[h=4]IMPORTANCE:[/h] Influenza viral infections represent a serious public health problem, with influenza virus causing a contagious respiratory disease that is most effectively prevented through vaccination. The multifunctional nonstructural protein 1 (NS1) is the main viral factor counteracting the host antiviral response. Therefore, influenza virus surveillance to identify new mutations in the NS1 protein affecting the pathogenicity of the circulating viruses is highly important. In this work, we evaluate amino acid variability in the NS1 proteins from H3N2 human seasonal viruses, and the effect of the mutations in innate immune responses and virus pathogenesis. NS1 mutations D189N, and V194I impaired the ability of the NS1 protein to inhibit general gene expression and recombinant viruses harboring these mutations, were attenuated in a mice model of influenza infection. Interestingly, a virus encoding the H3N2 V194I NS1 protein demonstrated a temperature-sensitive phenotype, further attenuating the virus in vivo.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 28003482 DOI: 10.1128/JVI.01930-16
[PubMed - as supplied by publisher]
[h=1]NS1 protein amino acid changes D189N and V194I affect interferon responses, thermosensitivity and virulence of circulating H3N2 human influenza A viruses.[/h] Nogales A[SUP]1[/SUP], Martinez-Sobrido L[SUP]1[/SUP], Topham DJ[SUP]2,[/SUP][SUP]1[/SUP], DeDiego ML[SUP]2,[/SUP][SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza NS1 protein is a non-structural, multifunctional protein that counteracts host innate immune responses, modulating virus pathogenesis. NS1 protein variability in subjects infected with H3N2 IAVs during the 2010/2011 season was analyzed, finding amino acid changes in residues 86, 189, and 194. The consequences of these mutations in the NS1-mediated inhibition of IFN responses, and the pathogenesis of the virus were evaluated, showing that NS1 mutations D189N, and V194I impaired the ability of the NS1 protein to inhibit general gene expression, most probably because these mutations decreased the binding of NS1 to the cleavage and polyadenylation specificity factor 30 (CPSF30). A recombinant A/Puerto Rico/8/34 (PR8) H1N1 virus encoding the H3N2 NS1-D189N protein was slightly attenuated, whereas the virus encoding the H3N2 V194I NS1 protein was further attenuated in mice. The higher attenuation of this virus could not be explained by differences in the ability of the two NS1 proteins to counteract host innate immune responses, indicating that another factor must be responsible. In fact, we showed that the virus encoding the H3N2 V194I NS1 protein demonstrated a temperature-sensitive (ts) phenotype, providing a most likely explanation for the stronger attenuation observed. As far as we know, this is the first time describing that a mutation in NS1 residue 194 confers a ts phenotype. These studies are relevant in order to identify new residues important for NS1 functions, and in human influenza virus surveillance to assess mutations affecting the pathogenicity of circulating viruses.
[h=4]IMPORTANCE:[/h] Influenza viral infections represent a serious public health problem, with influenza virus causing a contagious respiratory disease that is most effectively prevented through vaccination. The multifunctional nonstructural protein 1 (NS1) is the main viral factor counteracting the host antiviral response. Therefore, influenza virus surveillance to identify new mutations in the NS1 protein affecting the pathogenicity of the circulating viruses is highly important. In this work, we evaluate amino acid variability in the NS1 proteins from H3N2 human seasonal viruses, and the effect of the mutations in innate immune responses and virus pathogenesis. NS1 mutations D189N, and V194I impaired the ability of the NS1 protein to inhibit general gene expression and recombinant viruses harboring these mutations, were attenuated in a mice model of influenza infection. Interestingly, a virus encoding the H3N2 V194I NS1 protein demonstrated a temperature-sensitive phenotype, further attenuating the virus in vivo.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 28003482 DOI: 10.1128/JVI.01930-16
[PubMed - as supplied by publisher]