Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells
Identifieur interne : 000708 ( Pmc/Corpus ); précédent : 000707; suivant : 000709Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells
Auteurs : Miao Jiang ; Pamela Österlund ; Veera Westenius ; Deyin Guo ; Minna M. Poranen ; Dennis H. Bamford ; Ilkka JulkunenSource :
- Journal of Virology [ 0022-538X ] ; 2019.
Abstract
In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.
Url:
DOI: 10.1128/JVI.01916-18
PubMed: 30463970
PubMed Central: 6364019
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells</title><author><name sortKey="Jiang, Miao" sort="Jiang, Miao" uniqKey="Jiang M" first="Miao" last="Jiang">Miao Jiang</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Osterlund, Pamela" sort="Osterlund, Pamela" uniqKey="Osterlund P" first="Pamela" last="Österlund">Pamela Österlund</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westenius, Veera" sort="Westenius, Veera" uniqKey="Westenius V" first="Veera" last="Westenius">Veera Westenius</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guo, Deyin" sort="Guo, Deyin" uniqKey="Guo D" first="Deyin" last="Guo">Deyin Guo</name><affiliation><nlm:aff id="aff3"><addr-line>School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Poranen, Minna M" sort="Poranen, Minna M" uniqKey="Poranen M" first="Minna M." last="Poranen">Minna M. Poranen</name><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bamford, Dennis H" sort="Bamford, Dennis H" uniqKey="Bamford D" first="Dennis H." last="Bamford">Dennis H. Bamford</name><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Julkunen, Ilkka" sort="Julkunen, Ilkka" uniqKey="Julkunen I" first="Ilkka" last="Julkunen">Ilkka Julkunen</name><affiliation><nlm:aff id="aff4"><addr-line>Institute of Biomedicine, University of Turku and Turku University Hospital, Turku, Finland</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30463970</idno><idno type="pmc">6364019</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364019</idno><idno type="RBID">PMC:6364019</idno><idno type="doi">10.1128/JVI.01916-18</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000708</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000708</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells</title><author><name sortKey="Jiang, Miao" sort="Jiang, Miao" uniqKey="Jiang M" first="Miao" last="Jiang">Miao Jiang</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Osterlund, Pamela" sort="Osterlund, Pamela" uniqKey="Osterlund P" first="Pamela" last="Österlund">Pamela Österlund</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westenius, Veera" sort="Westenius, Veera" uniqKey="Westenius V" first="Veera" last="Westenius">Veera Westenius</name><affiliation><nlm:aff id="aff1"><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guo, Deyin" sort="Guo, Deyin" uniqKey="Guo D" first="Deyin" last="Guo">Deyin Guo</name><affiliation><nlm:aff id="aff3"><addr-line>School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Poranen, Minna M" sort="Poranen, Minna M" uniqKey="Poranen M" first="Minna M." last="Poranen">Minna M. Poranen</name><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bamford, Dennis H" sort="Bamford, Dennis H" uniqKey="Bamford D" first="Dennis H." last="Bamford">Dennis H. Bamford</name><affiliation><nlm:aff id="aff2"><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Julkunen, Ilkka" sort="Julkunen, Ilkka" uniqKey="Julkunen I" first="Ilkka" last="Julkunen">Ilkka Julkunen</name><affiliation><nlm:aff id="aff4"><addr-line>Institute of Biomedicine, University of Turku and Turku University Hospital, Turku, Finland</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30463970</article-id><article-id pub-id-type="pmc">6364019</article-id><article-id pub-id-type="publisher-id">01916-18</article-id><article-id pub-id-type="doi">10.1128/JVI.01916-18</article-id><article-categories><subj-group subj-group-type="heading"><subject>Vaccines and Antiviral Agents</subject></subj-group></article-categories><title-group><article-title>Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells</article-title><alt-title alt-title-type="running-head">Dicer-Substrate siRNA Swarm Inhibits Influenza Virus</alt-title><alt-title alt-title-type="short-authors">Jiang et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Jiang</surname><given-names>Miao</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-2229-6661</contrib-id><name><surname>Österlund</surname><given-names>Pamela</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Westenius</surname><given-names>Veera</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Deyin</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Poranen</surname><given-names>Minna M.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bamford</surname><given-names>Dennis H.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Julkunen</surname><given-names>Ilkka</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><aff id="aff1"><label>a</label><addr-line>Expert Microbiology Unit, Department of Health Security, National Institute for Health and Welfare, Helsinki, Finland</addr-line></aff><aff id="aff2"><label>b</label><addr-line>Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff3"><label>c</label><addr-line>School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China</addr-line></aff><aff id="aff4"><label>d</label><addr-line>Institute of Biomedicine, University of Turku and Turku University Hospital, Turku, Finland</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Schultz-Cherry</surname><given-names>Stacey</given-names></name><role>Editor</role><aff>St. Jude Children's Research Hospital</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Miao Jiang, <email>miao.jiang@helsinki.fi</email>, or Ilkka Julkunen, <email>ilkka.julkunen@utu.fi</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Jiang M, Österlund P, Westenius V, Guo D, Poranen MM, Bamford DH, Julkunen I. 2019. Efficient inhibition of avian and seasonal influenza A viruses by a virus-specific Dicer-substrate small interfering RNA swarm in human monocyte-derived macrophages and dendritic cells. J Virol 93:e01916-18. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01916-18">https://doi.org/10.1128/JVI.01916-18</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>21</day><month>11</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>5</day><month>2</month><year>2019</year></pub-date><pub-date pub-type="collection"><day>15</day><month>2</month><year>2019</year></pub-date><volume>93</volume><issue>4</issue><elocation-id>e01916-18</elocation-id><history><date date-type="received"><day>30</day><month>10</month><year>2018</year></date><date date-type="accepted"><day>9</day><month>11</month><year>2018</year></date></history><permissions><copyright-statement>Copyright © 2019 American Society for Microbiology.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder><license license-type="asm" xlink:href="https://doi.org/10.1128/ASMCopyrightv2"><license-p><ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/ASMCopyrightv2">All Rights Reserved</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="JVI.01916-18.pdf"></self-uri><abstract abstract-type="precis"><p>In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.</p></abstract><abstract><title>ABSTRACT</title><p>Influenza A viruses (IAVs) are viral pathogens that cause epidemics and occasional pandemics of significant mortality. The generation of efficacious vaccines and antiviral drugs remains a challenge due to the rapid appearance of new influenza virus types and antigenic variants. Consequently, novel strategies for the prevention and treatment of IAV infections are needed, given the limitations of the presently available antivirals. Here, we used enzymatically produced IAV-specific double-stranded RNA (dsRNA) molecules and <named-content content-type="genus-species">Giardia intestinalis</named-content> Dicer for the generation of a swarm of small interfering RNA (siRNA) molecules. The siRNAs target multiple conserved genomic regions of the IAVs. In mammalian cells, the produced 25- to 27-nucleotide-long siRNA molecules are processed by endogenous Dicer into 21-nucleotide siRNAs and are thus designated Dicer-substrate siRNAs (DsiRNAs). We evaluated the efficacy of the above DsiRNA swarm at preventing IAV infections in human primary monocyte-derived macrophages and dendritic cells. The replication of different IAV strains, including avian influenza H5N1 and H7N9 viruses, was significantly inhibited by pretransfection of the cells with the IAV-specific DsiRNA swarm. Up to 7 orders of magnitude inhibition of viral RNA expression was observed, which led to a dramatic inhibition of IAV protein synthesis and virus production. The IAV-specific DsiRNA swarm inhibited virus replication directly through the RNA interference pathway although a weak induction of innate interferon responses was detected. Our results provide direct evidence for the feasibility of the siRNA strategy and the potency of DsiRNA swarms in the prevention and treatment of influenza, including the highly pathogenic avian influenza viruses.</p><p><bold>IMPORTANCE</bold> In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>Dicer-substrate siRNA</kwd><kwd>DsiRNA</kwd><kwd>RNA interference</kwd><kwd>avian influenza virus</kwd><kwd>gene silencing</kwd><kwd>human macrophage</kwd><kwd>human moDC</kwd><kwd>influenza A virus</kwd><kwd>IAV</kwd><kwd>interferon response</kwd><kwd>IFN</kwd><kwd>siRNA swarm</kwd><kwd>viral replication</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>Jane and Aatos Erkko Foundation</institution></institution-wrap></funding-source><principal-award-recipient><name><surname>Poranen</surname><given-names>Minna M.</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source><institution-wrap><institution>Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)</institution><institution-id>https://doi.org/10.13039/501100006306</institution-id></institution-wrap></funding-source><principal-award-recipient><name><surname>Poranen</surname><given-names>Minna M.</given-names></name></principal-award-recipient></award-group><award-group id="award3"><funding-source><institution-wrap><institution>Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)</institution><institution-id>https://doi.org/10.13039/501100006306</institution-id></institution-wrap></funding-source><principal-award-recipient><name><surname>Julkunen</surname><given-names>Ilkka</given-names></name></principal-award-recipient></award-group><award-group id="award4"><funding-source><institution-wrap><institution>Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)</institution><institution-id>https://doi.org/10.13039/501100006306</institution-id></institution-wrap></funding-source><principal-award-recipient><name><surname>Bamford</surname><given-names>Dennis H.</given-names></name></principal-award-recipient></award-group><award-group id="award5"><funding-source><institution-wrap><institution>Ella ja Georg Ehrnroothin Säätiö (Ella and Georg Ehrnrooth Foundation)</institution><institution-id>https://doi.org/10.13039/501100003502</institution-id></institution-wrap></funding-source><principal-award-recipient><name><surname>Jiang</surname><given-names>Miao</given-names></name></principal-award-recipient></award-group><award-group id="award6"><funding-source><institution-wrap><institution>Academy of Finland (Suomen Akatemia)</institution><institution-id>https://doi.org/10.13039/501100002341</institution-id></institution-wrap></funding-source><award-id>252252</award-id><principal-award-recipient><name><surname>Julkunen</surname><given-names>Ilkka</given-names></name></principal-award-recipient></award-group><award-group id="award7"><funding-source><institution-wrap><institution>Academy of Finland (Suomen 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