title: H7N9 Influenza A Virus Exhibits Importin-α7-Mediated Replication in the Mammalian Respiratory Tract.
abstract: The acute respiratory distress syndrome (ARDS) is the leading cause of death in influenza A virus (IAV)-infected patients. Hereby, the cellular importin-α7 gene plays a major role. It promotes viral replication in the lung, thereby increasing the risk for the development of pneumonia complicated by ARDS. Herein, we analyzed whether the recently emerged H7N9 avian IAV has already adapted to human importin-α7 use, which is associated with high-level virus replication in the mammalian lung. Using a cell-based viral polymerase activity assay, we could detect a decreased H7N9 IAV polymerase activity when importin-α7 was silenced by siRNA. Moreover, virus replication was diminished in the murine cells lacking the importin-α7 gene. Consistently, importin-α7 knockout mice presented reduced pulmonary virus titers and lung lesions as well as enhanced survival rates compared to wild-type mice. In summary, our results show that H7N9 IAV have acquired distinct features of adaptation to human host factors that enable enhanced virulence in mammals. In particular, adaptation to human importin-α7 mediates elevated virus replication in the mammalian lung, which might have contributed to ARDS observed in H7N9-infected patients.
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Center for Structural and Cellular Biology in Medicine, University of Lübeck, Lübeck, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bertram
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Swantje
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Dreier
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Resa-Infante
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Preuß
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Debby
authors.initials: D
authors.lastname: van Riel
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; The University of Hong Kong-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chris K P
authors.initials: CKP
authors.lastname: Mok
authors.affiliation: Institute of Virology, Philipps University Marburg, Marburg, Germany.
authors.forename: Folker
authors.initials: F
authors.lastname: Schwalm
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; The University of Hong Kong-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Joseph S M
authors.initials: JSM
authors.lastname: Peiris
authors.affiliation: Institute of Virology, Philipps University Marburg, Marburg, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Center for Structural and Cellular Biology in Medicine, University of Lübeck, Lübeck, Germany. Electronic address: guelsah.gabriel@hpi.uni-hamburg.de.
authors.forename: Gülsah
authors.initials: G
authors.lastname: Gabriel
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D064766:Influenza A Virus, H7N9 Subtype / Q000472:pathogenicity / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008322:Mammals / Q000821:virology*; D051379:Mice; D012137:Respiratory System / Q000378:metabolism* / Q000821:virology*; D014774:Virulence; D014779:Virus Replication; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D028901:alpha Karyopherins; D004259:DNA-Directed DNA Polymerase