Figure 2. . Intracellular signaling by PRRs leads to chemokine, cytokine and interferon responses.

Endosomal TLR3 and TLR7 induce two signaling pathways leading to type I IFN and cytokines responses. Although TLR3 and TLR7 induce similar responses against DENV, they use different adapter molecules to induce gene expression. TLR3 associates with TRIF, while TLR7 forms a complex with MYD88. CLEC5A is a potent inducer of cytokines via adapter molecules DAP10 and DAP12. This leads to the activation of kinases Syk and Akt and the induction of IL-6, TNF, CCL3 and CXCL8. In addition, CLEC5A activates NLRP3 inflammasomes, which process pro IL-1β and IL-18 into maturate IL-1β and IL-18, respectively. DC-SIGN signaling in response to manosylated ligands involves adapter protein LSP1 and kinase Raf-1. DC-SIGN triggering modulates NFκB activation via Raf-1 and possibly enhances CLEC5A-mediated IL-1β, IL-6 and TNF production. Direct MR activation leads to IL-10 production, although it does not contain a known signaling motif. RIG-I and MDA5 signal via adapter molecule MAVS to induce two distinct signaling pathways. One pathway leads to IL-1β, IL-6, TNF, CCL2, CLL3, CLL4 expression while the other signaling pathway involves kinases TBK1 and IKKε to induce type I and type III IFN. Notably, RLR-induced type I IFN triggers IFNα/βR signaling via JAK/STAT which is modulated by RLR-activated IKKε to induce IL-27 in addition to antiviral ISGs. In the absence of RLR-IFNα/βR crosstalk, IFNα/βR signaling leads to ISGs induction without IL-27.

ISGs: IFN-stimulated genes; MR: Mannose receptor.