Статья

Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses

N. Ilyushina, V. Lugovtsev, A. Samsonova, F. Sheikh, N. Bovin, R. Donnelly,
2021

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. © 2017, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  • 1. Version of Record от 2021-04-27

Метаданные

Об авторах
  • N. Ilyushina
    Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
  • V. Lugovtsev
    Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
  • A. Samsonova
    Carbohydrate Chemistry Laboratory, Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
  • F. Sheikh
  • N. Bovin
  • R. Donnelly
Название журнала
  • PLoS ONE
Том
  • 12
Выпуск
  • 7
Страницы
  • -
Ключевые слова
  • interferon regulatory factor 3; interleukin 28A; interleukin 29; phosphoprotein; retinoic acid inducible protein I; STAT1 protein; virus sialidase; antivirus agent; DDX58 protein, human; DNA directed RNA polymerase; IL29 protein, human; interferon regulatory factor 3; interleukin derivative; IRF3 protein, human; retinoic acid inducible protein I; sialidase; STAT1 protein; STAT1 protein, human; virus receptor; animal cell; antiviral resistance; Article; controlled study; embryo; enzyme activity; gene; gene expression; human; human cell; IFNB1 gene; IFNL1 gene; IFNL2 gene; IFNL3 gene; Influenza A virus (H1N1); nonhuman; protein phosphorylation; virus characterization; virus mutation; virus replication; virus strain; amino acid substitution; animal; antiviral resistance; cell line; DNA sequence; dog; drug effects; enzyme linked immunosorbent assay; gene expression regulation; genetic recombination; genetics; growth, development and aging; Influenza A virus (H1N1); innate immunity; metabolism; mutation; phosphorylation; physiology; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; DEAD Box Protein 58; DNA-Directed RNA Polymerases; Dogs; Drug Resistance, Viral; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Immunity, Innate; Influenza A Virus, H1N1 Subtype; Interferon Regulatory Factor-3; Interleukins; Mutation; Neuraminidase; Phosphorylation; Receptors, Virus; Recombination, Genetic; Sequence Analysis, DNA; STAT1 Transcription Factor; Virus Replication
Издатель
  • Public Library of Science
Тип документа
  • journal article
Тип лицензии Creative Commons
  • CC
Правовой статус документа
  • Свободная лицензия
Источник
  • scopus