Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses
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...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0181999 |
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| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0181999 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0181999</identifier><identifier>PMID: 28750037</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Substitution - genetics ; Analysis ; Animals ; Antiviral activity ; Antiviral Agents - pharmacology ; Biology and life sciences ; Cell Line ; DEAD Box Protein 58 - metabolism ; DNA-Directed RNA Polymerases - metabolism ; Dogs ; Dosage and administration ; Drug resistance ; Drug Resistance, Viral - drug effects ; Enzymatic activity ; Enzyme activity ; Enzyme-Linked Immunosorbent Assay ; Epithelial cells ; Exo-a-sialidase ; Gene expression ; Gene Expression Regulation - drug effects ; Health risks ; Humans ; Immunity, Innate - drug effects ; Influenza ; Influenza A ; Influenza A Virus, H1N1 Subtype - drug effects ; Influenza A Virus, H1N1 Subtype - genetics ; Influenza A Virus, H1N1 Subtype - growth & development ; Influenza A Virus, H1N1 Subtype - physiology ; Influenza viruses ; Interferon ; Interferon regulatory factor 3 ; Interferon Regulatory Factor-3 - metabolism ; Interferons ; Interleukins - pharmacology ; Kinases ; Lungs ; Medicine and health sciences ; Microbial drug resistance ; Mutants ; Mutation ; Mutation - genetics ; Neuraminidase - genetics ; Orthomyxoviridae ; Pandemics ; Phosphorylation ; Phosphorylation - drug effects ; Physiological aspects ; Proteins ; Receptors, Immunologic ; Receptors, Virus - genetics ; Recombination, Genetic - genetics ; Sequence Analysis, DNA ; Stat1 protein ; STAT1 Transcription Factor - metabolism ; Tyrosine ; Virus Replication - drug effects ; Viruses</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0181999</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>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. 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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. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28750037</pmid><doi>10.1371/journal.pone.0181999</doi><orcidid>https://orcid.org/0000-0001-8178-0472</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2017529305 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Substitution - genetics Analysis Animals Antiviral activity Antiviral Agents - pharmacology Biology and life sciences Cell Line DEAD Box Protein 58 - metabolism DNA-Directed RNA Polymerases - metabolism Dogs Dosage and administration Drug resistance Drug Resistance, Viral - drug effects Enzymatic activity Enzyme activity Enzyme-Linked Immunosorbent Assay Epithelial cells Exo-a-sialidase Gene expression Gene Expression Regulation - drug effects Health risks Humans Immunity, Innate - drug effects Influenza Influenza A Influenza A Virus, H1N1 Subtype - drug effects Influenza A Virus, H1N1 Subtype - genetics Influenza A Virus, H1N1 Subtype - growth & development Influenza A Virus, H1N1 Subtype - physiology Influenza viruses Interferon Interferon regulatory factor 3 Interferon Regulatory Factor-3 - metabolism Interferons Interleukins - pharmacology Kinases Lungs Medicine and health sciences Microbial drug resistance Mutants Mutation Mutation - genetics Neuraminidase - genetics Orthomyxoviridae Pandemics Phosphorylation Phosphorylation - drug effects Physiological aspects Proteins Receptors, Immunologic Receptors, Virus - genetics Recombination, Genetic - genetics Sequence Analysis, DNA Stat1 protein STAT1 Transcription Factor - metabolism Tyrosine Virus Replication - drug effects Viruses |
| title | Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T22%3A16%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Generation%20and%20characterization%20of%20interferon-lambda%201-resistant%20H1N1%20influenza%20A%20viruses&rft.jtitle=PloS%20one&rft.au=Ilyushina,%20Natalia%20A&rft.date=2017-07-27&rft.volume=12&rft.issue=7&rft.spage=e0181999&rft.pages=e0181999-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0181999&rft_dat=%3Cgale_plos_%3EA499460481%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2017529305&rft_id=info:pmid/28750037&rft_galeid=A499460481&rft_doaj_id=oai_doaj_org_article_2c516d0fe02f4b2598146900a8b03271&rfr_iscdi=true |