• Can the use of transgenic animals containing the natural resistance gene(s) of mallard ducks prevent pathogenic influenza virus infection? Non-Hemagglutinating Flaviviruses: Molecular Mechanisms for the Emergence of New Strains via Adaptation to European Ticks Tick-borne encephalitis virus (TBEV) causes human epidemics across Eurasia. Clinical manifestations range from inapparent infections and fevers to fatal encephalitis but the factors that determine disease severity are currently undefined. TBEV is characteristically a hemagglutinating (HA) virus; the ability to agglutinate erythrocytes tentatively reflects virion receptor/fusion activity. However, for the past few years many atypical HA-deficient strains have been isolated from patients and also from the natural European host tick, Ixodes persulcatus. By analysing the sequences of HA-deficient strains we have identified 3 unique amino acid substitutions (D67G, E122G or D277A) in the envelope protein, each of which increases the net charge and hydrophobicity of the virion surface. Therefore, we genetically engineered virus mutants each containing one of these 3 substitutions; they all exhibited HA-deficiency. Unexpectedly, each genetically modified non-HA virus demonstrated increased TBEV reproduction in feeding Ixodes ricinus, not the recognised tick host for these strains. Moreover, virus transmission efficiency between infected and uninfected ticks co-feeding on mice was also intensified by each substitution. Retrospectively, the mutation D67G was identified in viruses isolated from patients with encephalitis. We propose that the emergence of atypical Siberian HA-deficient TBEV strains in Europe is linked to their molecular adaptation to local ticks. This process appears to be driven by the selection of single mutations that change the virion surface thus enhancing receptor/fusion function essential for TBEV entry into the unfamiliar tick species. As the consequence of this adaptive mutagenesis, some of these mutations also appear to enhance the ability of TBEV to cross the human blood-brain barrier, a likely explanation for fatal encephalitis. Future research will reveal if these emerging Siberian TBEV strains continue to disperse westwards across Europe by adaptation to the indigenous tick species and if they are associated with severe forms of TBE. Tick-borne encephalitis virus (TBEV) causes up to 14,000 human cases of tick-borne encephalitis (TBE) across Eurasia annually [1, 2] . TBE outbreaks are now registered in about 30 European countries with a recorded morbidity increase of about 400% during the past 30 years [3] . TBEV is a member of the tick-borne flavivirus (TBFV) group that, together with mosquito-borne and no-known vector virus groups comprise the genus Flavivirus within the family Flaviviridae. Human pathogens within the genus Flavivirus include Japanese encephalitis virus, Dengue virus and Yellow fever virus that cause annual epidemics of fever, encephalitis and hemorrhagic fever in the tropics and some sub-tropical regions [4, 5] .