Interferons Induce STAT1–Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease

• Published in: The Journal of infectious diseases 2016-05, Vol.213 (10), p.1632-1641
• Main Authors: Strandin, Tomas, Hepojoki, Jussi, Laine, Outi, Mäkelä, Satu, Klingström, Jonas, Lundkvist, Åke, Julkunen, Ilkka, Mustonen, Jukka, Vaheri, Antti
• Format: Article
• Language: English
• Subjects: Animals; Cercopithecus aethiops; Cohort Studies; Endothelial Cells - metabolism; Gene Expression Regulation, Viral; Hantavirus; hemorrhagic fever; Hemorrhagic Fever with Renal Syndrome - metabolism; Hemorrhagic Fever with Renal Syndrome - virology; Humans; innate immunity; interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Macaca; Macaca fascicularis; PATHOGENESIS AND HOST RESPONSE; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Puumala virus - pathogenicity; Signal Transduction; STAT1; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; tissue plasminogen activator; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism; Up-Regulation; Vero Cells; Virulence Factors
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiv764

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.