Biology of Zika Virus Infection in Human Skin Cells

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Abstract
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family that includes Dengue, West Nile, Yellow Fever and Japanese encephalitis viruses, causing a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here, we determine the importance of the human skin in the entry of ZIKV and its contribution to the induction of anti-viral 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, among which DC-SIGN, AXL, TYRO3, and to a lesser extent, TIM-1, permitted ZIKV entry with a major role for the TAM receptor AXL. ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing Ab and specific RNA silencing. ZIKV induced the transcription of TLR-3, RIG-I and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15 and MX1, characterized by a strongly enhanced interferon-β gene expression. ZIKV was found to be sensitive to the antiviral effect 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 or the specific autophagy inhibitor 3-Methyladenine. The results presented herein permit to gain better insight in the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging Flavivirus.