Zoonotic viruses represent a major global health challenge. Climate change, growing populations, and increased travel bring humans into closer contact with animal vectors that carry infectious diseases. In Europe, this is especially evident with arthropod-borne (arbo)viruses. Warmer Mediterranean climates have allowed tropical mosquito-borne viruses to become endemic and they now threaten to spread further north. At the same time, milder climates in Northern Europe extend the season of tick activity, creating more opportunities for tick-borne viruses to circulate. To address these growing risks, new strategies against arboviruses are needed, beginning with a better understanding of how viruses such as tick-borne encephalitis virus (TBEV) replicate in their hosts.
The interactions between the RNA that carries the genetic information of RNA viruses and their hosts have long been underestimated. Yet a central question remains: how can a molecule so fragile as viral RNA adapt to the constantly changing environments in which it replicates—shifts in temperature and cellular conditions—throughout infection? For neurotropic Orthoflaviviruses such as TBEV, this challenge is especially striking. The virus must adapt to dramatic changes: from a dormant tick that overwinters and becomes active at mild temperatures, to about 34 °C during tick feeding, and finally to 37 °C in humans. Within this cycle, TBEV first replicates in the tick midgut, then spreads to the salivary glands for transmission. Once the female tick bites, TBEV infects skin cells at the feeding site, spreads through the body via immune cells, and eventually reaches the central nervous system, where it can cause severe disease.
To investigate these processes, we studied TBEV RNA from three complementary perspectives in relevant models: (1) its interactome, to identify interacting host proteins involved in viral replication, (2) its structure, to understand its shape and interactions with the host, and (3) its sequence adaptation to pinpoint regions under different selective pressures. We compared two immune cell models in which TBEV replication may be restricted: one monocytic cell line derived from circulating blood cells and one microglial cell line derived from the central nervous system, and also included a neuronal cell line, in which TBEV replicates efficiently. For comparison to human cells, we used whole female ticks collected in the wild.
