title: Interferons Induce STAT1-Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease.
abstract: Hantaviruses are zoonotic viruses that show various degrees of vasculopathy in humans. In this study, we analyzed the regulation of 2 fibrinolytic parameters, tissue plasminogen activator (tPA) and its physiological inhibitor, plasminogen activator inhibitor 1 (PAI-1), in Puumala hantavirus (PUUV)-infected patients and in human microvascular endothelial cells. We detected strong upregulation of tPA in the acute phase of illness and in PUUV-infected macaques and found the tPA level to positively correlate with disease severity. The median levels of PAI-1 during the acute stage did not differ from those during the recovery phase. In concordance, hantaviruses induced tPA but not PAI-1 in microvascular endothelial cells, and the induction was demonstrated to be dependent on type I interferon. Importantly, type I and II interferons directly upregulated tPA through signal transducer and activator of transcription 1 (STAT1), which regulated tPA gene expression via a STAT1-responsive enhancer element. These results suggest that tPA may be a general factor in the immunological response to viruses.
authors.affiliation: Department of Virology, Faculty of Medicine, University of Helsinki.
authors.forename: Tomas
authors.initials: T
authors.lastname: Strandin
authors.affiliation: Department of Virology, Faculty of Medicine, University of Helsinki.
authors.forename: Jussi
authors.initials: J
authors.lastname: Hepojoki
authors.affiliation: School of Medicine, University of Tampere Department of Internal Medicine, Tampere University Hospital.
authors.forename: Outi
authors.initials: O
authors.lastname: Laine
authors.affiliation: School of Medicine, University of Tampere Department of Internal Medicine, Tampere University Hospital.
authors.forename: Satu
authors.initials: S
authors.lastname: Mäkelä
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm.
authors.forename: Jonas
authors.initials: J
authors.lastname: Klingström
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lundkvist
authors.affiliation: Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki Department of Virology, University of Turku, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.affiliation: School of Medicine, University of Tampere Department of Internal Medicine, Tampere University Hospital.
authors.forename: Jukka
authors.initials: J
authors.lastname: Mustonen
authors.affiliation: Department of Virology, Faculty of Medicine, University of Helsinki.
authors.forename: Antti
authors.initials: A
authors.lastname: Vaheri
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D042783:Endothelial Cells / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006480:Hemorrhagic Fever with Renal Syndrome / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D029262:Puumala virus / Q000472:pathogenicity*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014709:Vero Cells; D037521:Virulence Factors
chemical_list: D007370:Interferon Type I; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D037521:Virulence Factors; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator
keywords: STAT1; hantavirus; hemorrhagic fever; innate immunity; interferon; tissue plasminogen activator