1% of infections) at the site of the bite of an infected tick, where Langerhans cells and macrophages in the skin are preferentially targeted. TBEV envelope (E) proteins recognize heparan sulfate (and likely other receptors) on the host cell surface and are endocytosed via the clathrin mediated pathway. Acidification of the late endosome triggers a conformational change in the E proteins, resulting in fusion, followed by uncoating, and release of the single-stranded RNA genome into the cytoplasm. The viral polyprotein is translated and inserts into the ER membrane, where it is processed on the cytosolic side by host peptidases and in the lumen by viral enzyme action. The viral proteins C, NS3, and NS5 are cleaved into the cytosol (though NS3 can complex with NS2B or NS4A to perform proteolytic or helicase activity), while the remaining nonstructural proteins alter the structure of the ER membrane. This altered membrane permits the assembly of replication complexes, where the viral genome is replicated by the viral RNA-dependent RNA polymerase, NS5. Newly replicated viral RNA genomes are then packaged by the C proteins while on the cytosolic side of the ER membrane, forming the immature nucleocapsid, and gain E and PrM proteins, arranged as a heterodimer, during budding into the lumen of the ER. The immature virion is spiky and geometric in comparison to the mature particle. The particle passes through the golgi apparatus and trans-golgi network, under increasingly acidic conditions, by which the virion matures with cleavage of the Pr segment from the M protein and formation fusion competent E protein homodimers. Though the cleaved Pr segment remains associated with protein complex until exit. The virus is released from the host cell upon fusion of the transport vesicle with the host cell membrane, the cleaved Pr now segments dissociate, resulting in a fully mature, infectious virus. However, partially mature and immature viruses are sometimes released as well; immature viruses are noninfectious as the E proteins are not fusion competent, partially mature viruses are still capable of infection. Pathogenesis and immune response With the exception of food-borne cases, infection begins in the skin at the site of the tick bite. Skin dendritic (or Langerhans) cells (DCs) are preferentially targeted. Initially, the virus replicates locally and immune response is triggered when viral components are recognized by cytosolic pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). Recognition causes the release of cytokines including interferons (IFN)