tetano
Editor, Senior Moderator
PLoS One. 2017 Jul 27;12(7):e0181999. doi: 10.1371/journal.pone.0181999. eCollection 2017.
[h=1]Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses.[/h] Ilyushina NA[SUP]1[/SUP], Lugovtsev VY[SUP]2[/SUP], Samsonova AP[SUP]2[/SUP], Sheikh FG[SUP]1[/SUP], Bovin NV[SUP]3[/SUP], Donnelly RP[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A viruses pose a constant potential threat to human health. In view of the innate antiviral activity of interferons (IFNs) and their potential use as anti-influenza agents, it is important to know whether viral resistance to these antiviral proteins can arise. To examine the likelihood of emergence of IFN-λ1-resistant H1N1 variants, we serially passaged the A/California/04/09 (H1N1) strain in a human lung epithelial cell line (Calu-3) in the presence of increasing concentrations of recombinant IFN-λ1 protein. To monitor changes associated with adaptation of this virus to growth in Calu-3 cells, we also passaged the wild-type virus in the absence of IFN-λ1. Under IFN-λ1 selective pressure, the parental virus developed two neuraminidase (NA) mutations, S79L and K331N, which significantly reduced NA enzyme activity (↓1.4-fold) and sensitivity to IFN-λ1 (↓˃20-fold), respectively. These changes were not associated with a reduction in viral replication levels. Mutants carrying either K331N alone or S79L and K331N together induced weaker phosphorylation of IFN regulatory factor 3 (IRF3), and, as a consequence, much lower expression of the IFN genes (IFNB1, IFNL1 and IFNL2/3) and proteins (IFN-λ1 and IFN-λ2/3). The lower levels of IFN expression correlated with weaker induction of tyrosine-phosphorylated STAT1 and reduced RIG-I protein levels. Our findings demonstrate that influenza viruses can develop increased resistance to the antiviral activity of type III interferons.
PMID: 28750037 DOI: 10.1371/journal.pone.0181999
[h=1]Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses.[/h] Ilyushina NA[SUP]1[/SUP], Lugovtsev VY[SUP]2[/SUP], Samsonova AP[SUP]2[/SUP], Sheikh FG[SUP]1[/SUP], Bovin NV[SUP]3[/SUP], Donnelly RP[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A viruses pose a constant potential threat to human health. In view of the innate antiviral activity of interferons (IFNs) and their potential use as anti-influenza agents, it is important to know whether viral resistance to these antiviral proteins can arise. To examine the likelihood of emergence of IFN-λ1-resistant H1N1 variants, we serially passaged the A/California/04/09 (H1N1) strain in a human lung epithelial cell line (Calu-3) in the presence of increasing concentrations of recombinant IFN-λ1 protein. To monitor changes associated with adaptation of this virus to growth in Calu-3 cells, we also passaged the wild-type virus in the absence of IFN-λ1. Under IFN-λ1 selective pressure, the parental virus developed two neuraminidase (NA) mutations, S79L and K331N, which significantly reduced NA enzyme activity (↓1.4-fold) and sensitivity to IFN-λ1 (↓˃20-fold), respectively. These changes were not associated with a reduction in viral replication levels. Mutants carrying either K331N alone or S79L and K331N together induced weaker phosphorylation of IFN regulatory factor 3 (IRF3), and, as a consequence, much lower expression of the IFN genes (IFNB1, IFNL1 and IFNL2/3) and proteins (IFN-λ1 and IFN-λ2/3). The lower levels of IFN expression correlated with weaker induction of tyrosine-phosphorylated STAT1 and reduced RIG-I protein levels. Our findings demonstrate that influenza viruses can develop increased resistance to the antiviral activity of type III interferons.
PMID: 28750037 DOI: 10.1371/journal.pone.0181999