Tick-borne encephalitis virus (TBEV) is responsible for about 3000 yearly human infections in Europe, where it is mostly transmitted by the Ixodes ricinus tick. Despite its simple molecular composition (ten proteins and a positive-stranded RNA genome measuring 11kb) TBEV can infect both ticks and humans, while they are very phylogenetically distant species. To date, it is not yet resolved how TBEV, and more broadly all arboviruses, can infect both an arthropod and a vertebrate host. This study aims to elucidate the molecular mechanisms driving TBEV infection in human and tick, by focusing on the identification of cellular proteins interacting with the viral genome. Although they are less studied than the interactions between viral proteins and host proteins, interactions between host proteins and viral RNA are critical for the viral lifecycle. The RNA genome indeed represents the core of viral multiplication, hijacking many cellular factors to ensure its translation and replication. On the other hand, the viral genome can be recognized and targeted by specific cellular sensors and effectors to eliminate the infection. We mapped the human and tick protein interactomes of TBEV genome using ChIRP-MS, an innovative technique allowing to identify RNA binding proteins in cellulo, during an infection. We highlighted many host-virus interactions, some of which were unknown. We are currently analyzing the functional role of the most robust interactions using RNA interference in human and tick cell lines, to characterize their impact on TBEV lifecycle. Our comparative study shall allow us to uncover new restriction or dependency factors of TBEV infection, some of which might be conserved between human and tick hosts, as well as more largely shed light on the ability of arboviruses to infect vertebrates and arthropods together.