Structural dynamics and antigenicity of the TBEV envelope

The surface of viral particles is composed of proteins that mediate entry of viruses into host cells to initiate the infection process. Antibodies that bind to these proteins can inhibit viral entry and thus neutralize the virus. There is increasing evidence that the viral surface is not a static structure but is in constant motion, also referred to as viral breathing. The oscillations of viral surface proteins can modulate the induction of antibodies and their interaction with the virus. In this project, we will address the question of viral breathing and its impact on antibody interactions with tick-borne encephalitis virus (TBEV), which causes an important arthropod- transmitted disease of humans. This virus is endemic in many parts of Europe, Central and Eastern Asia and is responsible for several thousand cases of hospitalizations annually. TBEV is closely related to groups of medically relevant mosquito-transmitted viruses (together referred to as flaviviruses), including dengue, Zika, yellow fever, Japanese encephalitis, and West Nile viruses. Flavivirus breathing was first shown for dengue viruses, including the demonstration of differences between naturally occurring variants of the virus. However, no such information is available for tick- borne flaviviruses. Although all flaviviruses are structurally related, there is evidence that the viruses differ with respect to the motions of their envelope proteins and therefore to the effect of breathing on antibody interactions. We will therefore investigate the structural dynamics of TBEV envelope proteins of prototype and naturally occurring viral strains and study the impact of their breathing on interactions with antibodies. The project will provide novel insights into particle dynamics of a tick-borne flavivirus and will contribute to a better understanding of factors influencing flavivirus neutralization, thus providing leads for the selection and/or design of novel vaccines.