Dengue virus (DENV) transmission occurs in two distinct cycles, the endemic/urban cycle, between human hosts and primarily Aedes (Ae.) aegypti mosquitoes, and the sylvatic cycle in non-human primates and their associated Aedes mosquitoes. With rapid urbanization and encroachment into sylvatic environments, there is increasing opportunity for spill-over events to occur. For infection to occur, DENV must evade the primary defences of the innate immune system in both mosquito and human hosts. However, it is poorly understood how the immune system of these two hosts might respond to sylvatic DENV infection. In this study, mosquito and human cell lines were infected with urban or sylvatic strains of DENV and the transcriptomic response investigated at two timepoints. Several common and unique differentially expressed genes (DEGs) were found, the number of which varied between DENV strain infections. The number of DEGs associated with immune response was found to be highly dependent on DENV strain, with no significant differences observed between urban and sylvatic DENV strains. In mosquito cells there was a notable increase in the number and expression level of long non-coding RNAs (lncRNAs) during infection. The immune response to sylvatic DENV in human cells is currently being analysed. Further investigation of sylvatic strains and their interaction with the host immune system will provide invaluable insight into the potential of sylvatic DENV spillover and establishment into endemic/urban human cycles.