**11. JAK-STAT pathway for JE**

IFN-α and IFN-β, play important role in recovery from flaviviral infections. However, they fail sometimes due to ability of JEV to inhibit the JAK-STAT (Janus kinase signal transducer and activator of transcription) pathway (Lin et al., 2006). Studies of DEN-2 antagonism of STAT1 phosphorylation have revealed NS4B as the primary and impor‐ tant antagonist. Still the exact mechanism of IFN antagonism is under study. The specific receptor complex for each IFN-α and IFN-β is composed of two major subunits and sev‐ eral JAK tyrosine kinases constitutively associated with the receptor. Jak1 and Jak2 are required for IFN-α/β signaling. Following binding of the receptor subunits by IFN, the JAKs trans-phosphorylate each other and then phosphorylate critical tyrosine residues within the intracellular domains of the receptor subunits (Lin et al., 2004). These phos‐ phorylated residues serve as recruitment sites for STAT proteins, which bind the activat‐ ed receptor and are in turn phosphorylated by the JAKs. The phosphorylated STAT proteins then form homodimers, or heterodimers, with other STAT proteins and translo‐ cate to the nucleus, where they bind specific DNA sequences within the promoter re‐ gions of IFN-stimulated genes (ISGs) (Fig. 5). ISG expression induces an antiviral state within the cell, can modulate cell proliferation and cell death, and modulates immune re‐ sponses via its roles in activation and maturation of antigen-presenting cells. The ability of the individual non-structural proteins to antagonize JAK-STAT signaling has been studied and results indicated that NS5 blocked STAT1 phosphorylation in response to ei‐ ther IFN-α or IFN-β which highlights the function of NS5 to have a critical role in virus pathogenesis (Best et al., 2005).

**Figure 5.** Displaying the JAK STAT Pathway. JAK STAT signaling pathway is important for transduction of information between cells carrying information for cellular differentiation and homeostasis. Cytokines and their receptors are the major activator of JAK/STAT pathway. IFN are antiviral cytokines produced by cells as soon as the onset of viral infec‐ tion. IFN-α and IFN-β bind to different receptors and, play important role in recovery from flaviviral infections. Howev‐ er, they fail sometimes due to ability of JEV to inhibit the JAK-STAT pathway.
