Protein Kinase R (PKR) One of the first reported WNV restriction factor was PKR, also known as EIF2AK2. cover most of the current knowledge on viral restriction factors as well as WNV evasion strategies in mosquito and human cells in order to bring an updated overview on WNVChost interactions. genus, which also comprises Zika computer virus (ZIKV), dengue computer virus (DENV), tick-borne encephalitis computer virus (TBEV), and yellow fever computer virus (YFV). All these viruses are transmitted by mosquitoes and are therefore known as arboviruses (for arthropod-borne viruses). WNV was first isolated in the West Nile district of Uganda in 1937 and has since spread across the world [1]. This enveloped computer virus has a 11-kb positive single-stranded RNA genome (ssRNA) that encodes three structural proteins (C, E, prM) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The viral genome is composed of only one single open reading frame (ORF), flanked by two untranslated regions (5 and 3 UTR). The flavivirus RNA genome is usually capped, but unlike cellular mRNA, it lacks a poly (A) tail. WNV, like the equally concerning Usutu computer virus [2,3], belongs to the Japanese encephalitis computer virus (JEV) serocomplex. It is maintained in nature in an enzootic cycle between mosquitoes of the genus as vectors, and birds as the main reservoir and amplifier hosts. Although mammals can be infected during a mosquito blood meal, these are considered as dead-end hosts since viral replication ends rapidly (short and low viremia). Sometimes, mosquitoes that have fed on infected birds can Penthiopyrad then accidentally transmit the computer virus to humans. Although mosquitoes are considered as the predominant vector for WNV, other mosquito genera, such as or model, whose immune system is usually well conserved with that of mosquitoes [34]. Mosquito innate immunity is mainly based on RNA interference (RNAi) pathways [35], which inhibit viral replication by RNA interference and secretion of the cytokine Vago [36,37]. These pathways involve small interfering RNAs (siRNA) [38], microRNAs (miRNA) [39], and P-element Induced Wimpy-interacting RNAs (PIWI-interacting RNAs, piRNA) [40]. In addition to RNAi, other mechanisms are also involved in innate defenses, including the toll, IMD (immune deficiency), and JAK/STAT pathways, which lead to the secretion of antimicrobial peptides. Mosquitoes are the vectors, and therefore key players, of WNV transmission. Once they ingest an infected blood meal on a viremic host, viral replication begins in the mosquito midgut epithelial cells and viral particles disseminate into hemolymph blood circulation to reach muscle tissue and the neural system. Salivary glands, which constitute the end-point tissue, carry high viral loads [41], which favors viral Rabbit Polyclonal to FGFR1/2 transmission during the next blood ingestion on a susceptible host [42]. The extrinsic incubation period, which is usually defined as the time between viral acquisition by a mosquito on a viremic host and the transmission of viral contamination to a susceptible host [43], is usually a key parameter in the control of WNV contamination. Thus, mosquito immunity can take action directly on this extrinsic incubation period, by limiting viral pathogenesis and dissemination to levels that are not detrimental for them. Indeed, recent studies from Carla Salehs lab have unraveled a very interesting mechanism taking place in mosquitoes to allow them to control viral pathogenesis. The viral genome is usually efficiently detected by Dicer-2 and then degraded by RNAi in mosquito cells. In addition, endogenous reverse transcriptases transcribe the viral genome or elements of the viral RNA into viral DNA, Penthiopyrad which is then integrated into the host genome or managed as Penthiopyrad extrachromosomal DNA (episome) [44]. This mechanism relies on active endogenous retrotransposons in insect cells, which harbor important basal retrotranscriptase activity. The viral DNA is usually then transcribed into RNA and recognized by Dicer-2, thus re-engaging and amplifying the RNAi response [45,46]. This initial mechanism controls the viral pathogenesis, allowing cell survival. The balance between antiviral immunity and viral escape that takes place in mosquitoes contributes to efficient viral transmission to a new host. Thus, mosquito cells carry a high viral load, notably into salivary glands [37,43], without displaying any symptoms. 2.2. Antiviral Factors and Viral Countermeasures In the context of WNV mosquito infection, only a few antiviral factors have been identified so far. In 2014, Yasunaga et al. performed a genome-wide RNAi screen in that led to the identification of several WNV restriction factors [47]. They demonstrated that dRUVBL1 (pontin/Tip49, an ATPase), dRUVBL2 (reptin/Tip48, another ATPase), Tip60 (histone acetylase), and dXOP1 (embargoed, a nuclear export receptor) had antiviral activity against.