Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species
Identifieur interne : 000322 ( Main/Exploration ); précédent : 000321; suivant : 000323Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species
Auteurs : Smanla Tundup [États-Unis] ; Matheswaran Kandasamy [États-Unis] ; Jasmine T. Perez [États-Unis] ; Nacho Mena [États-Unis] ; John Steel [États-Unis] ; Tamas Nagy [États-Unis] ; Randy A. Albrecht [États-Unis] ; Balaji Manicassamy [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2017.
Abstract
The cellular and molecular mechanisms underpinning the unusually high virulence of highly pathogenic avian influenza H5N1 viruses in mammalian species remains unknown. Here, we investigated if the cell tropism of H5N1 virus is a determinant of enhanced virulence in mammalian species. We engineered H5N1 viruses with restricted cell tropism through the exploitation of cell type-specific microRNA expression by incorporating microRNA target sites into the viral genome. Restriction of H5N1 replication in endothelial cells via miR-126 ameliorated disease symptoms, prevented systemic viral spread and limited mortality, despite showing similar levels of peak viral replication in the lungs as compared to control virus-infected mice. Similarly, restriction of H5N1 replication in endothelial cells resulted in ameliorated disease symptoms and decreased viral spread in ferrets. Our studies demonstrate that H5N1 infection of endothelial cells results in excessive production of cytokines and reduces endothelial barrier integrity in the lungs, which culminates in vascular leakage and viral pneumonia. Importantly, our studies suggest a need for a combinational therapy that targets viral components, suppresses host immune responses, and improves endothelial barrier integrity for the treatment of highly pathogenic H5N1 virus infections.
Url:
DOI: 10.1371/journal.ppat.1006270
PubMed: 28282445
PubMed Central: 5362246
Affiliations:
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Perez</name><affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Department of Microbiology, University of Chicago, Chicago, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, University of Chicago, Chicago, IL</wicri:regionArea><placeName><region type="state">Illinois</region><settlement type="city">Chicago</settlement></placeName><orgName type="university">Université de Chicago</orgName></affiliation></author><author><name sortKey="Mena, Nacho" sort="Mena, Nacho" uniqKey="Mena N" first="Nacho" last="Mena">Nacho Mena</name><affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Steel, John" sort="Steel, John" uniqKey="Steel J" first="John" last="Steel">John Steel</name><affiliation wicri:level="2"><nlm:aff id="aff004"><addr-line>Department of Microbiology, Emory University, Atlanta, GA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Emory University, Atlanta, GA</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Nagy, Tamas" sort="Nagy, Tamas" uniqKey="Nagy T" first="Tamas" last="Nagy">Tamas Nagy</name><affiliation wicri:level="2"><nlm:aff id="aff005"><addr-line>Comparative Pathology Laboratory, University of Georgia, Athens, GA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comparative Pathology Laboratory, University of Georgia, Athens, GA</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Albrecht, Randy A" sort="Albrecht, Randy A" uniqKey="Albrecht R" first="Randy A." last="Albrecht">Randy A. Albrecht</name><affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Manicassamy, Balaji" sort="Manicassamy, Balaji" uniqKey="Manicassamy B" first="Balaji" last="Manicassamy">Balaji Manicassamy</name><affiliation wicri:level="4"><nlm:aff id="aff001"><addr-line>Department of Microbiology, University of Chicago, Chicago, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, University of Chicago, Chicago, IL</wicri:regionArea><placeName><region type="state">Illinois</region><settlement type="city">Chicago</settlement></placeName><orgName type="university">Université de Chicago</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff002"><addr-line>Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL</wicri:regionArea><placeName><region type="state">Illinois</region><settlement type="city">Chicago</settlement></placeName><orgName type="university">Université de Chicago</orgName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The cellular and molecular mechanisms underpinning the unusually high virulence of highly pathogenic avian influenza H5N1 viruses in mammalian species remains unknown. Here, we investigated if the cell tropism of H5N1 virus is a determinant of enhanced virulence in mammalian species. We engineered H5N1 viruses with restricted cell tropism through the exploitation of cell type-specific microRNA expression by incorporating microRNA target sites into the viral genome. Restriction of H5N1 replication in endothelial cells via miR-126 ameliorated disease symptoms, prevented systemic viral spread and limited mortality, despite showing similar levels of peak viral replication in the lungs as compared to control virus-infected mice. Similarly, restriction of H5N1 replication in endothelial cells resulted in ameliorated disease symptoms and decreased viral spread in ferrets. Our studies demonstrate that H5N1 infection of endothelial cells results in excessive production of cytokines and reduces endothelial barrier integrity in the lungs, which culminates in vascular leakage and viral pneumonia. Importantly, our studies suggest a need for a combinational therapy that targets viral components, suppresses host immune responses, and improves endothelial barrier integrity for the treatment of highly pathogenic H5N1 virus infections.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author><author><name sortKey="Kash, Jc" uniqKey="Kash J">JC Kash</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author><author><name sortKey="Bean, Wj" uniqKey="Bean W">WJ Bean</name></author><author><name sortKey="Gorman, Ot" uniqKey="Gorman O">OT Gorman</name></author><author><name sortKey="Chambers, Tm" uniqKey="Chambers T">TM Chambers</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y 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Brownlee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neumann, G" uniqKey="Neumann G">G Neumann</name></author><author><name sortKey="Watanabe, T" uniqKey="Watanabe T">T Watanabe</name></author><author><name sortKey="Ito, H" uniqKey="Ito H">H Ito</name></author><author><name sortKey="Watanabe, S" uniqKey="Watanabe S">S Watanabe</name></author><author><name sortKey="Goto, H" uniqKey="Goto H">H Goto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perez, Jt" uniqKey="Perez J">JT Perez</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A Garcia-Sastre</name></author><author><name sortKey="Manicassamy, B" uniqKey="Manicassamy B">B Manicassamy</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li><li>Illinois</li><li>État de New York</li></region><settlement><li>Chicago</li></settlement><orgName><li>Université de Chicago</li></orgName></list><tree><country name="États-Unis"><region name="Illinois"><name sortKey="Tundup, Smanla" sort="Tundup, Smanla" uniqKey="Tundup S" first="Smanla" last="Tundup">Smanla Tundup</name></region><name sortKey="Albrecht, Randy A" sort="Albrecht, Randy A" uniqKey="Albrecht R" first="Randy A." last="Albrecht">Randy A. Albrecht</name><name sortKey="Kandasamy, Matheswaran" sort="Kandasamy, Matheswaran" uniqKey="Kandasamy M" first="Matheswaran" last="Kandasamy">Matheswaran Kandasamy</name><name sortKey="Kandasamy, Matheswaran" sort="Kandasamy, Matheswaran" uniqKey="Kandasamy M" first="Matheswaran" last="Kandasamy">Matheswaran Kandasamy</name><name sortKey="Manicassamy, Balaji" sort="Manicassamy, Balaji" uniqKey="Manicassamy B" first="Balaji" last="Manicassamy">Balaji Manicassamy</name><name sortKey="Manicassamy, Balaji" sort="Manicassamy, Balaji" uniqKey="Manicassamy B" first="Balaji" last="Manicassamy">Balaji Manicassamy</name><name sortKey="Mena, Nacho" sort="Mena, Nacho" uniqKey="Mena N" first="Nacho" last="Mena">Nacho Mena</name><name sortKey="Nagy, Tamas" sort="Nagy, Tamas" uniqKey="Nagy T" first="Tamas" last="Nagy">Tamas Nagy</name><name sortKey="Perez, Jasmine T" sort="Perez, Jasmine T" uniqKey="Perez J" first="Jasmine T." last="Perez">Jasmine T. Perez</name><name sortKey="Steel, John" sort="Steel, John" uniqKey="Steel J" first="John" last="Steel">John Steel</name><name sortKey="Tundup, Smanla" sort="Tundup, Smanla" uniqKey="Tundup S" first="Smanla" last="Tundup">Smanla Tundup</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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