Dengue virus replication in infected human keratinocytes leads to activation of antiviral innate immune responses.

Dengue virus (DENV) infection is the most prevalent mosquito-borne viral diseases in the world. Vector-mediated transmission of DENV is initiated when a blood-feeding female Aedes mosquito injects saliva, together with the virus, into the skin of its mammalian host. Understanding the role of skin immune cells in the activation of innate immunity to DENV at the early times of infection is a critical issue that remains to be investigated. The purpose of our study was to assess the contribution of human keratinocytes as potential host cells to DENV in the activation of immune responses at the anatomical site of mosquito bite. We show that primary keratinocytes support DENV replication with the production of negative-stranded viral RNAs inside the infected cells. In the course of DENV life cycle, we observed the activation of host genes involved in the antiviral immune responses such as intracellular RNA virus sensors Toll-Like Receptor-3, Retinoic Acid Inducible Gene-I, Melanoma Differentiation Associated gene-5 and the RNA-dependent protein kinase R. DENV infection of primary keratinocytes also resulted in up-regulation of the expression of the antiviral Ribonuclease L gene, which subsequently led to enhanced production of IFN-β and IFN-γ. Depending on stages of viral replication, we observed the activation of host genes encoding the antimicrobial proteins β-defensin and RNase 7 in infected keratinocytes. Our data demonstrate for the first time the permissiveness of human epidermal keratinocytes to DENV infection. Remarkably, DENV replication in keratinocytes contributes to the establishment of antiviral innate immunity that might occur in the early times after the bite of mosquito.

Surasombatpattana P ，Hamel R ，Patramool S ，Luplertlop N ，Thomas F ，Desprès P ，Briant L ，Yssel H ，Missé D ... -  《-》

Biology of Zika Virus Infection in Human Skin Cells.

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family, which includes dengue, West Nile, yellow fever, and Japanese encephalitis viruses, that causes a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here we examine the importance of human skin in the entry of ZIKV and its contribution to the induction of antiviral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, including DC-SIGN, AXL, Tyro3, and, to a lesser extent, TIM-1, permitted ZIKV entry, with a major role for the TAM receptor AXL. The ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing antibody and specific RNA silencing. ZIKV induced the transcription of Toll-like receptor 3 (TLR3), RIG-I, and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15, and MX1, characterized by strongly enhanced beta interferon gene expression. ZIKV was found to be sensitive to the antiviral effects of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes, whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy, and the specific autophagy inhibitor 3-methyladenine. The results presented herein permit us to gain further insight into the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging flavivirus. Zika virus (ZIKV) is an arbovirus belonging to the Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor and for cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide the first general insights into the interaction between ZIKV and its mammalian host.

Hamel R ，Dejarnac O ，Wichit S ，Ekchariyawat P ，Neyret A ，Luplertlop N ，Perera-Lecoin M ，Surasombatpattana P ，Talignani L ，Thomas F ，Cao-Lormeau VM ，Choumet V ，Briant L ，Desprès P ，Amara A ，Yssel H ，Missé D ... -  《-》

Rhodiola inhibits dengue virus multiplication by inducing innate immune response genes RIG-I, MDA5 and ISG in human monocytes.

Diwaker D ，Mishra KP ，Ganju L ，Singh SB ... -  《-》

Protein kinase regulated by dsRNA downregulates the interferon production in dengue virus- and dsRNA-stimulated human lung epithelial cells.

Li Y ，Xie J ，Wu S ，Xia J ，Zhang P ，Liu C ，Zhang P ，Huang X ... -  《PLoS One》

DDX50 inhibits the replication of dengue virus 2 by upregulating IFN-β production.

Han P ，Ye W ，Lv X ，Ma H ，Weng D ，Dong Y ，Cheng L ，Chen H ，Zhang L ，Xu Z ，Lei Y ，Zhang F ... -  《-》