Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

Tibor Füzik¹, Petra Formanová², Daniel Růžek^2,3, Kentaro Yoshii⁴, Matthias Niedrig⁵, Pavel Plevka¹

¹ Structural Virology, Central European Institute of Technology, Masaryk University, Kamenice 753/5, 62500 Brno, Czech Republic

² Department of Virology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic

³ Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, 37005 Ceske Budejovice, Czech Republic

⁴ Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan

⁵ Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany

Tick-borne encephalitis virus (TBEV) causes 13,000 cases of human meningitis and encephalitis annually. However, the structure of the TBEV virion and its interactions with antibodies are unknown. Here, we present cryo-EM structures of the native TBEV virion and its complex with Fab fragments of neutralizing antibody 19/1786. Flavivirus genome delivery depends on membrane fusion that is triggered at low pH. The virion structure indicates that the repulsive interactions of histidine side chains, which become protonated at low pH, may contribute to the disruption of heterotetramers of the TBEV envelope and membrane proteins and induce detachment of the envelope protein ectodomains from the virus membrane. The Fab fragments bind to 120 out of the 180 envelope glycoproteins of the TBEV virion. Unlike most of the previously studied flavivirus-neutralizing antibodies, the Fab fragments do not lock the E-proteins in the native-like arrangement, but interfere with the process of virus-induced membrane fusion.