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

Dittmann et al. Cell 2015; 160: 631-43.

Speaker: Guan-Yu Chen (陳冠宇)                               Time: 14:00~15:00, May 20, 2015

Commentator: Dr. Jen-Ren Wang (王貞仁老師)         Place: Room 601

Abstract

Influenza occurs all over the world annually with high mutation rates and frequent genetic reassortment. When cells are infected by influenza virus, they produce interferons, which trigger transcription of hundreds of interferon-stimulated genes (ISGs). These ISGs have been shown to contribute to antiviral activities, and most of the functions of ISGs are focused on the early steps of viral infection, such as entry or virus replication (1). In this study, the authors used a high-throughput microscopy screening of 401 ISG cDNAs to identify ISGs that inhibit late stages of influenzaA virus (IAV) infection. They discovered a well-known gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1) and plays a role in regulation of fibrinolysis (2). IAV infection led to upregulation of PAI-1 secretion, and extracellular PAI-1 could reduce IAV infection. PAI-1 could target trypsin-like airway proteases, which are necessary for extracellular IAV maturation. Cleavage of HA0 into HA1 and HA2 and maturation of IAV progeny particles were blocked by PAI-1 binding to proteases. Moreover, Serpine1 was upregulated and the expression of PAI-1 was also increased upon IAV infection in mice. Notably, Serpine1^-/- mice were more susceptible to IAV infection, exhibiting enhanced IAV infection and more severe disease pathology. Human fibroblasts from donors with single nucleotide polymorphism (SNP) rs6092, which is located in SERPINE1 (c.A43T) and results in partial intracellular retention of PAI-1, conferred increased susceptibility to IAV in vitro. In conclusion, PAI-1 can inhibit IAV spread by targeting proteases and blocking maturation of IAV progeny particles, suggesting that management of PAI-1 location might be a new target to treat IAV or other respiratory viruses.

References:

1.     Schneider WM. et al. Interferon-stimulated genes: a complex web of host defenses. Ann. Rev. Immunol. 2014; 32: 513-45.

2.     Yildiz SY. et al. Functional stability of plasminogen activator inhibitor-1. ScientificWorldJournal 2014; 2014: 858293.