A Serpin Shapes the Extracellular Environment to Prevent Influenza A Virus Maturation

• Published in: Cell Vol. 160; no. 4; pp. 631 - 643
• Main Authors: Dittmann, Meike, Hoffmann, Hans-Heinrich, Scull, Margaret A., Gilmore, Rachel H., Bell, Kierstin L., Ciancanelli, Michael, Wilson, Sam J., Crotta, Stefania, Yu, Yingpu, Flatley, Brenna, Xiao, Jing W., Casanova, Jean-Laurent, Wack, Andreas, Bieniasz, Paul D., Rice, Charles M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2015
• Subjects: Animals; Cell Line; genes; glycoproteins; Humans; Immunity, Innate; Influenza A virus; Influenza A virus - physiology; Mice, Inbred C57BL; pathogenicity; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; plasminogen activator inhibitors; progeny; proteinases; Respiratory System - enzymology; Respiratory System - virology; Serine Proteases - metabolism; Serpin E2 - genetics; Serpin E2 - metabolism; viruses
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.01.040

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. [Display omitted] •SERPINE1/PAI-1 was identified as an unconventional ISG that acts extracellularly•PAI-1 inhibits influenza A virus (IAV) spread by inhibiting glycoprotein cleavage•Endogenous PAI-1 blocks IAV spread in human and murine cells, ex vivo and in vivo•PAI-1 potentially inhibits other viruses requiring extracellular maturation Plasminogen activator inhibitor (PAI-1) blocks surface glycoprotein maturation of influenza A virus, thus reducing virus spread in the airways and revealing that the innate immune system, driven by type I IFN, uses modulation of the extracellular environment to inhibit viruses.