title: A serpin shapes the extracellular environment to prevent influenza A virus maturation.
abstract: Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response.
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Meike
authors: M
authors: Dittmann
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Hans-Heinrich
authors: HH
authors: Hoffmann
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Margaret A
authors: MA
authors: Scull
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Rachel H
authors: RH
authors: Gilmore
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Kierstin L
authors: KL
authors: Bell
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors: Michael
authors: M
authors: Ciancanelli
authors: Howard Hughes Medical Institute, Laboratory of Retrovirology, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors: Sam J
authors: SJ
authors: Wilson
authors: Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors: Stefania
authors: S
authors: Crotta
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Yingpu
authors: Y
authors: Yu
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Brenna
authors: B
authors: Flatley
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
authors: Jing W
authors: JW
authors: Xiao
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Imagine Institute, Inserm, 75015 Paris, France; Paris Descartes University, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors: Andreas
authors: A
authors: Wack
authors: Howard Hughes Medical Institute, Laboratory of Retrovirology, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA.
authors: Paul D
authors: PD
authors: Bieniasz
authors: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@rockefeller.edu.
authors: Charles M
authors: CM
authors: Rice
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000502:physiology*; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000201:enzymology / Q000821:virology; D057057:Serine Proteases / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D057057:Serine Proteases