John Libbey Eurotext

European Cytokine Network

Skin innate immune response to flaviviral infection Volume 28, numéro 2, June 2017

Figure 1

Schematic first steps of Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses inoculation through the human skin, replication and induction of inflammatory response. Following the probe of an infected mosquito, the virus can replicate in keratinocytes (DENV, WNV and ZIKV), fibroblasts (DENV, WNV and ZIKV), skin dendritic cells (DENV and WNV), Langerhans cells, dermal dendritic cells and mast cells (DENV) inducing an antiviral response mainly constituted of type I and III IFNs, IL4, IL1β, IL6, CCL5, IL8, CXCL10, CXCL11 and antimicrobial peptides such as defensin 5, hBD2 and 3. Mast cell and fibroblast infection by DENV can lead to endothelial cell activation and proliferation via secretion of VEGF. In return, endothelial cells can secrete soluble mediators able to inhibit DENV replication.

Figure 2

Innate immune response to Dengue (DENV), Zika (ZIKV) and West Nile (WNV) viruses in human skin cells. After viral binding to the host receptor, viral single-stranded (ss) and double-stranded (ds) RNA generated during genome replication can be sensed by host cells’ pattern recognition receptors (PRRs). RIG-I can detect both ss and ds RNA whereas MDA5 can detect dsRNA. These cytosolic PRR activation lead to signaling downstream via IPS-1 and NF-κB nuclear translocation contributing to expression of chemokines, cytokines, type I interferon (IFN) and interferon-stimulated genes (ISGs). Extracellular ds and ssRNA can also be detected respectively by Toll-Like Receptor (TLR)3 and TLR7 in the endosomal compartment, which hetero- or homodimerize upon their activation. After recruitment of the adaptor molecule, TIR domain-containing adaptor inducing IFN β (TRIF), TLR3 signaling pathway enables nuclear translocation of NF-κB, IFN regulatory factor (IRF)3 and 7 to promote ISGs and type I and III IFN gene expression. TLR7 activation induces MyD88 recruitment and downstream signaling involving IRAK1 or IKKα and IRF7. Finally, in an autocrine (but also paracrine) way, type I IFN binds to IFNα and β receptor (IFNAR), amplifying cell antiviral state by promoting ISGs and type I IFN gene expression, including the IRF7 gene.