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Rift Valley fever phlebovirus (RVFV) causes an emerging zoonotic disease and is mainly transmitted by Culex and Aedes mosquitoes. While Aedes aegypti-dengue virus (DENV) is the most studied model, less is known about the genes involved in infection-responses in other mosquito-arboviruses pairing. The main objective was to investigate the molecular responses of Cx. pipiens to RVFV exposure focusing mainly on genes implicated in innate immune responses. Mosquitoes were fed with blood spiked with RVFV. The fully-engorged females were pooled at 3 different time points: 2 hours post-exposure (hpe), 3- and 14-days post-exposure (dpe). Pools of mosquitoes fed with non-infected blood were also collected for comparisons. Total RNA from each mosquito pool was subjected to RNA-seq analysis and a de novo transcriptome was constructed. A total of 451 differentially expressed genes (DEG) were identified. Most of the transcriptomic alterations were found at an early infection stage after RVFV exposure. Forty-eight DEG related to immune infection-response were characterized. Most of them were related with the RNAi system, Toll and IMD pathways, ubiquitination pathway and apoptosis. Our findings provide for the first time a comprehensive view on Cx. pipiens-RVFV interactions at the molecular level. The early depletion of RNAi pathway genes at the onset of the RVFV infection would allow viral replication in mosquitoes. While genes from the Toll and IMD immune pathways were altered in response to RVFV none of the DEG were related to the JAK/STAT pathway. The fact that most of the DEG involved in the Ubiquitin-proteasome pathway (UPP) or apoptosis were found at an early stage of infection would suggest that apoptosis plays a regulatory role in infected Cx. pipiens midguts. This study provides a number of target genes that could be used to identify new molecular targets for vector control. Author summary: Rift valley fever (RVF) is an emerging zoonotic disease and it is caused by RVFV. This virus is commonly transmitted in endemic areas between wild ruminants and mosquitoes, mainly by mosquitoes of Culex and Aedes genus. Starting from the year 2000, several outbreaks have been reported outside Sub Saharan Africa, in countries facing the Mediterranean Sea (Egypt), or Yemen and Saudi Arabia. Available vaccines for ruminants present limited efficacy or residual pathogenic effects. Consequently, new strategies are urgently required to limit the expansion of this zoonotic virus. The main objective of this work is to investigate transcriptional alterations of Cx. pipiens to RVFV focusing mainly on genes implicated in conventional innate immunity pathways, RNAi mechanisms and the apoptotic process in order to evaluate the involvement of these genes in viral infection. The immune altered genes here described could be potential targets to control RVFV infection in mosquitoes. Some of the genes related to the immune defense response were previously described in others mosquito-arbovirus models, as well as in Drosophila and human. To our knowledge, this study highlights for the first time the Cx. pipiens-RVFV interactions in terms of defense infection-response and provides information for developing in the future new approaches to prevent and control the expansion of the virus. [ABSTRACT FROM AUTHOR]