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Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses.
- Source :
-
PloS one [PLoS One] 2017 Jul 27; Vol. 12 (7), pp. e0181999. Date of Electronic Publication: 2017 Jul 27 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Amino Acid Substitution genetics
Animals
Antiviral Agents pharmacology
Cell Line
DEAD Box Protein 58 metabolism
DNA-Directed RNA Polymerases metabolism
Dogs
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation drug effects
Humans
Immunity, Innate drug effects
Influenza A Virus, H1N1 Subtype drug effects
Influenza A Virus, H1N1 Subtype growth & development
Interferon Regulatory Factor-3 metabolism
Interferons
Mutation genetics
Neuraminidase genetics
Phosphorylation drug effects
Receptors, Immunologic
Receptors, Virus genetics
Recombination, Genetic genetics
STAT1 Transcription Factor metabolism
Sequence Analysis, DNA
Virus Replication drug effects
Drug Resistance, Viral drug effects
Influenza A Virus, H1N1 Subtype genetics
Influenza A Virus, H1N1 Subtype physiology
Interleukins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 12
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 28750037
- Full Text :
- https://doi.org/10.1371/journal.pone.0181999