α, β , and γ and chemokines, attracting migratory immune cells to the site of the bite. The infection may be halted at this stage and cleared, before the onset of noticeable symptoms. Notably, tick saliva enhances infection by modulating host immune response, dampening apoptotic signals. If the infection continues, migratory DCs and macrophages become infected and travel to the local draining lymph node where activation of polymorphonuclear leukocytes, monocytes and the complement system are activated. The draining lymph node can also serve as a viral amplification site, from where TBEV gains systemic access. This viremic stage corresponds to the first symptomatic phase in the prototypical biphasic pattern of tick-borne encephalitis. TBEV has a strong preference for neuronal tissue, and is neuroinvasive. The initial viremic stage allows access to a number of the preferential tissues. However, the exact mechanism by which TBEV crosses into the central nervous system (CNS) is unclear. There are several proposed mechanism for TBEV breaching the blood-brain barrier (BBB): 1)The "Trojan Horse" mechanism, whereby TBEV gains access to the CNS while infecting an immune cell that passes through the BBB; 2) Disruption and increased permeability of the BBB by immune immune cytokines; 3) Via infection of the olfactory neurons; 4) Via retrograde transport along peripheral nerves to the CNS; 5) Infection of the cells that make up part of the BBB. CNS infection brings on the second phase in the classic biphasic infection pattern associated with the European subtype. CNS disease is immunopathological; release of inflammatory cytokines coupled with the action of cytotoxic CD8+ T cells and possibly NK cells results in inflammation and apoptosis of infected cells that is responsible for many of the CNS symptoms. Humoral response TBEV specific IgM and IgG antibodies are produced in response to infection. IgM antibodies appear and peak first, as well as reaching higher levels, and typically dissipate in about 1.5 months post infection, though there exists considerable variation from patient to patient. IgG levels peak at about 6 weeks after the appearance of CNS symptoms, then decline slightly but do not dissipate, likely conferring life long immunity to the patient. Evolution The ancestor of the extant strains appears to have separated into several clades approximately 2750 years ago. The Siberian and Far Eastern subtypes diverged about 2250 years ago. A second analysis suggests an earlier date of evolution (3300 years ago) with a rapid increase in the