Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects

Lindqvist, Richard; Mundt, Filip; Gilthorpe, Jonathan D.; Wölfel, Silke; Gekara, Nelson O.; Kröger, Andrea; Överby, Anna K.

The genus Flavivirus belonging to the family Flaviviridae include important pathogens causing severe human disease including meningitis, encephalitis, hemorrhagic fevers, and microcephaly. The most significant neurotropic flaviviruses are arthropod-borne tick-borne encephalitis virus (TBEV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). TBEV is transmitted by Ixodes ticks, whereas WNV, JEV, and ZIKV are transmitted via mosquitos. No treatments are available for any of these viral infections, and patients are dependent on innate and adaptive parts of the host immune response to fight infections [1] [2] [3] [4] [5] [6] . The innate immune system presents a first line of defense against viral infections, for which type I interferons (IFNs) are particularly important. After flavivirus infection, double-stranded RNA (dsRNA) is produced as an intermediate during viral replication. This is sensed as a danger signal in the infected cell by pattern recognition receptors (PRRs) and a signaling cascade is initiated, which leads to the upregulation of IFNs [7, 8] . IFNs are powerful cytokines that mediate antiviral effects via both autocrine and paracrine signaling mechanisms via the IFN alpha receptor (IFNAR). Binding to IFNAR activates the downstream kinases Janus kinase 1 and tyrosine kinase 2, which phosphorylate signal transducer and activator of transcription-1 and transcription-2 (STAT1, STAT2). Together with interferon regulatory factor-9 (IRF9), these form a signaling complex referred to as IFN-stimulated gene factor-3 (ISGF3). ISGF3 translocates to the nucleus and activates the transcription of a large number of interferon-stimulated genes (ISGs) by binding to the interferon response elements. ISGs can inhibit almost every step of a viral life cycle [9, 10] .