Page 97 - TBE_Book_V2_2019

Chapter 4: Pathogenesis of TBE

Figure 4: Interferon (IFN) signaling and inhibition

The active IFN receptor is composed of 2 subunits, IFNAR1 and IFNAR2. Prolidase (PEPD) is required for
IFNAR1 maturation and intracellular trafficking to the plasma membrane (PM). Once IFNα/β binds to the
IFNAR1/2, JAK1 and TYK2 becomes phosphorylated, which then results in phosphorylation of STAT1 and 2.
This leads to dimerization of STAT and a signaling cascade that results in upregulation of ISG expression (left
panel). In TBEV- and LGTV-infected cells (right panel) the IFN antagonist NS5 binds to PEPD, thus preventing
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IFNAR1 transport to the PM, and IFNα/β signaling. NS5 also interferes with JAK1, TYK2, and STAT1
phosphorylation upon IFNα/β stimulation, thereby inhibiting ISG production. 55,56

nucleus to transcribe IFNβ, which then is ISGs that can limit the infection. The ISGs
translated and secreted (Figure 2). encode for PRR, adaptors and transcription
factors to ensure a rapid response after
Thus, the virus is produced and released from infection. Cytokines and chemokines are also
the cell before IFNβ can trigger an antiviral produced which activate and recruit immune
response in neighboring cells. 28,38 cells to limit the infection, as well as antiviral
proteins that can target viral replication
Type I IFN signaling and response against 39
directly in the cell. The IFNAR is therefore a
TBEV
key molecule in the type I IFN response. The
importance of this molecule has been demon-
After infection and secretion of IFN, the IFN strated for many viruses. For LGTV the type I
binds to its receptor the IFNAR1/2 which
stimulates the upregulation of hundreds of IFN response determines tropism and can

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