Figure 3. . Immune evasion by DENV.

DENV immune evasion by nonstructural (NS) proteins targets RLR signaling and IFNα-βR activation. After internalization, DENV replication is initiated which is detected by cytoplasmic sensors RIG-I and MDA5. These associate with adapter molecule MAVS (and possibly STING) to activate kinases TBK1 and IKKε leading to IRF transcription factor activation for type I IFN responses consisting of IFN-α and IFN-β. In parallel, NFκB transcription factors are activated that lead to cytokine and chemokine responses. Secreted type I IFN triggers STAT1 and STAT2-dependent IFNα/βR signaling leading to the induction of ISGs. Multiple steps in this process are inhibited by DENV NS proteins. RIG-I-MAVS association is inhibited by NS4A binding to MAVS. In addition, adapter protein STING is degraded by NS2B/3 which also inhibits the phosphorylation of IKKε. IKKε, in combination with TBK1, is further targeted by NS2A and NS4B to prevent their phosphorylation and activation via unknown mechanisms. IFNα/βR signaling is targeted by inhibiting the phosphorylation of STAT1 by NS4B and STAT2 by NS5. In addition, NS5 routes STAT2 for proteosomal degradation via the host protein UBR4. Moreover, activation of antiviral pathways can possibly be inhibited by host receptors. DC-SIGN activation can inhibit RIG-I and MDA5 activation via kinase Raf-1 and FcγR can inhibit IFNα/βR signaling via SOCS3-mediated inhibition of JAK.

DENV: Dengue virus; ISGs: Interferon-stimulated genes; MR: Mannose receptor.