Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge
Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through mic...
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| Veröffentlicht in: | Gene therapy 2015-08, Vol.22 (8), p.653-662 |
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| creator | Zhang, H Tang, X Zhu, C Song, Y Yin, J Xu, J Ertl, H C J Zhou, D |
| description | Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through microRNAs (miRNA) is an emerging technology that can suppress virus replication
in vitro
and
in vivo
. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals. |
| doi_str_mv | 10.1038/gt.2015.31 |
| format | Article |
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in vitro
and
in vivo
. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/gt.2015.31</identifier><identifier>PMID: 25835311</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 42 ; 42/89 ; 631/326/590 ; 692/699/255 ; Adenoviridae - genetics ; Adenoviridae - immunology ; Adenoviridae - metabolism ; Adenovirus ; Adenoviruses ; Advertising executives ; Animals ; Avian influenza ; Avian influenza viruses ; Biomedical and Life Sciences ; Biomedicine ; Cell Biology ; Cell Line, Tumor ; Drug delivery systems ; Female ; Gene Expression ; Gene Therapy ; Genetic aspects ; Genetic Vectors ; Genomes ; Genomics ; Health aspects ; HEK293 Cells ; House mouse ; Human Genetics ; Humans ; Infection ; Influenza ; Influenza A ; Influenza A virus ; Influenza A Virus, H1N1 Subtype - metabolism ; Influenza A Virus, H5N1 Subtype - metabolism ; Influenza A Virus, H9N2 Subtype - metabolism ; Influenza viruses ; Kidneys ; Mice, Inbred C57BL ; MicroRNA ; MicroRNAs ; MicroRNAs - immunology ; MicroRNAs - metabolism ; miRNA ; Nanotechnology ; Nuclear Matrix - genetics ; Nuclear Matrix - metabolism ; Nucleoproteins - genetics ; Nucleoproteins - metabolism ; original-article ; Pan troglodytes ; Prevention ; Preventive medicine ; Prophylaxis ; Public health ; Public health movements ; Replication ; RNA ; RNA interference ; RNA-mediated interference ; Technology ; Vectors (Biology) ; Virus replication</subject><ispartof>Gene therapy, 2015-08, Vol.22 (8), p.653-662</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c743t-119bb00b6164118a58453e51f9cdf279e3f71536d47b716696ca2dea5019cec33</citedby><cites>FETCH-LOGICAL-c743t-119bb00b6164118a58453e51f9cdf279e3f71536d47b716696ca2dea5019cec33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/gt.2015.31$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/gt.2015.31$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25835311$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, H</creatorcontrib><creatorcontrib>Tang, X</creatorcontrib><creatorcontrib>Zhu, C</creatorcontrib><creatorcontrib>Song, Y</creatorcontrib><creatorcontrib>Yin, J</creatorcontrib><creatorcontrib>Xu, J</creatorcontrib><creatorcontrib>Ertl, H C J</creatorcontrib><creatorcontrib>Zhou, D</creatorcontrib><title>Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><addtitle>Gene Ther</addtitle><description>Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through microRNAs (miRNA) is an emerging technology that can suppress virus replication
in vitro
and
in vivo
. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals.</description><subject>13/109</subject><subject>42</subject><subject>42/89</subject><subject>631/326/590</subject><subject>692/699/255</subject><subject>Adenoviridae - genetics</subject><subject>Adenoviridae - immunology</subject><subject>Adenoviridae - metabolism</subject><subject>Adenovirus</subject><subject>Adenoviruses</subject><subject>Advertising executives</subject><subject>Animals</subject><subject>Avian influenza</subject><subject>Avian influenza viruses</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Drug delivery systems</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic aspects</subject><subject>Genetic Vectors</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>House mouse</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Infection</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Influenza A virus</subject><subject>Influenza A Virus, H1N1 Subtype - metabolism</subject><subject>Influenza A Virus, H5N1 Subtype - metabolism</subject><subject>Influenza A Virus, H9N2 Subtype - metabolism</subject><subject>Influenza viruses</subject><subject>Kidneys</subject><subject>Mice, Inbred C57BL</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - immunology</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Nanotechnology</subject><subject>Nuclear Matrix - genetics</subject><subject>Nuclear Matrix - metabolism</subject><subject>Nucleoproteins - genetics</subject><subject>Nucleoproteins - metabolism</subject><subject>original-article</subject><subject>Pan troglodytes</subject><subject>Prevention</subject><subject>Preventive medicine</subject><subject>Prophylaxis</subject><subject>Public health</subject><subject>Public health movements</subject><subject>Replication</subject><subject>RNA</subject><subject>RNA interference</subject><subject>RNA-mediated interference</subject><subject>Technology</subject><subject>Vectors (Biology)</subject><subject>Virus replication</subject><issn>0969-7128</issn><issn>1476-5462</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNk1trFDEUxwdR7Fp98QNIQBAvzJqTTJKZx6V4KVSFqs8hmzkzmzKbqUlGqh_Az222W8uuSpU8hJz88j8n51IUD4HOgfL6ZZ_mjIKYc7hVzKBSshSVZLeLGW1kUypg9UFxL8YzSmmlana3OGCi5oIDzIofixb9-NWFKZZrbJ1J2BITkuucdWYg75wN4-n7RSTJhB6T8z1ZmxTcBRkD8ZMdcDwPY0LnSY8eI7k82UTWziIxvXE-JjJgWmU157thQv_dkEuPxGbjgL7H-8WdzgwRH1zth8Xn168-Hb0tTz68OT5anJRWVTyVAM1ySelSgqwAaiPqSnAU0DW27ZhqkHcKBJdtpZYKpGykNaxFIyg0Fi3nh8XTrW6O8suEMem1ixaHwXgcp6hBMQaqqWr1HyhlUoCQG9XHv6Fn4xR8_ohmnIMEJav6JiprQV2rKpfzmurNgDonbEzB2I1rvZBAGRWK3UxVubrAJGWZmv-FyqvFXJ3RY-eyfe_Bs70HmUl4kXozxaiPP57uh_Avdlf3yQ67QjOkVRyHKbnRx33RG8FdxedbMLdnjAE7fR7c2oRvGqjeTIXuk95MheaQ4UdXmZ-Wucmv0V9jkIEXWyDmq9yOYac0f8r9BMRbDz0</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Zhang, H</creator><creator>Tang, X</creator><creator>Zhu, C</creator><creator>Song, Y</creator><creator>Yin, J</creator><creator>Xu, J</creator><creator>Ertl, H C J</creator><creator>Zhou, D</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>7QO</scope></search><sort><creationdate>20150801</creationdate><title>Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge</title><author>Zhang, H ; Tang, X ; Zhu, C ; Song, Y ; Yin, J ; Xu, J ; Ertl, H C J ; Zhou, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c743t-119bb00b6164118a58453e51f9cdf279e3f71536d47b716696ca2dea5019cec33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13/109</topic><topic>42</topic><topic>42/89</topic><topic>631/326/590</topic><topic>692/699/255</topic><topic>Adenoviridae - genetics</topic><topic>Adenoviridae - immunology</topic><topic>Adenoviridae - metabolism</topic><topic>Adenovirus</topic><topic>Adenoviruses</topic><topic>Advertising executives</topic><topic>Animals</topic><topic>Avian influenza</topic><topic>Avian influenza viruses</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Drug delivery systems</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Genetic aspects</topic><topic>Genetic Vectors</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Health aspects</topic><topic>HEK293 Cells</topic><topic>House mouse</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Infection</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Influenza A virus</topic><topic>Influenza A Virus, H1N1 Subtype - metabolism</topic><topic>Influenza A Virus, H5N1 Subtype - metabolism</topic><topic>Influenza A Virus, H9N2 Subtype - 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Academic</collection><collection>Biotechnology Research Abstracts</collection><jtitle>Gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, H</au><au>Tang, X</au><au>Zhu, C</au><au>Song, Y</au><au>Yin, J</au><au>Xu, J</au><au>Ertl, H C J</au><au>Zhou, D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge</atitle><jtitle>Gene therapy</jtitle><stitle>Gene Ther</stitle><addtitle>Gene Ther</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>22</volume><issue>8</issue><spage>653</spage><epage>662</epage><pages>653-662</pages><issn>0969-7128</issn><eissn>1476-5462</eissn><abstract>Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through microRNAs (miRNA) is an emerging technology that can suppress virus replication
in vitro
and
in vivo
. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25835311</pmid><doi>10.1038/gt.2015.31</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0969-7128 1476-5462 |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | 13/109 42 42/89 631/326/590 692/699/255 Adenoviridae - genetics Adenoviridae - immunology Adenoviridae - metabolism Adenovirus Adenoviruses Advertising executives Animals Avian influenza Avian influenza viruses Biomedical and Life Sciences Biomedicine Cell Biology Cell Line, Tumor Drug delivery systems Female Gene Expression Gene Therapy Genetic aspects Genetic Vectors Genomes Genomics Health aspects HEK293 Cells House mouse Human Genetics Humans Infection Influenza Influenza A Influenza A virus Influenza A Virus, H1N1 Subtype - metabolism Influenza A Virus, H5N1 Subtype - metabolism Influenza A Virus, H9N2 Subtype - metabolism Influenza viruses Kidneys Mice, Inbred C57BL MicroRNA MicroRNAs MicroRNAs - immunology MicroRNAs - metabolism miRNA Nanotechnology Nuclear Matrix - genetics Nuclear Matrix - metabolism Nucleoproteins - genetics Nucleoproteins - metabolism original-article Pan troglodytes Prevention Preventive medicine Prophylaxis Public health Public health movements Replication RNA RNA interference RNA-mediated interference Technology Vectors (Biology) Virus replication |
| title | Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge |
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