**5. Pathogenesis and pathology**

After the bite of an infected tick TBEV replication occurs locally. Dendritic cells (Langerhans cells) are considered to be the most important cells for local viral replication and to transport the virus to the regional lymph nodes where further replication takes place. After release into the bloodstream the virus disseminate to other organs, in particular to the reticulo-endothelial system (mainly bone marrow, spleen, and liver) where the virus continue to multiply and maintain viremia for few days. During the viremic phase (which clinically matches to the initial phase of TBE) the virus probably reaches the brain [38, 39]. The precise mechanism of viral passage through the blood-brain barrier is unclear, but depends on the presence of viremia. Four possible routes have been postulated: (i) peripheral nerves, (ii) highly susceptible olfactory neurons (especially relevant in laboratory infections by aerosols), (iii) transcytosis through vascular endothelial cells of brain capillaries, and (iv) diffusion of the virus between capillary endothelial cells. The primary targets of TBEV infection in central nervous system are neurons. Rarely, oligodendrocytes are infected [38].

TBEV in CNS induces inflammation with inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The exact mechanism of tissue destruction is unclear, but Ružek and coworkers demonstrated that inflammatory reaction mediated by CD8+ T cells significantly contributes to neuronal damage [40]. Limited data are available on the role of cytokines and chemokines.

Pathological lesions are widespread all over the CNS and involve leptomeninges and gray matter, with the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord being most frequently affected. Histological findings are nonspecific; lesions consist of perivascular and parenchymal accumulation of lymphocytes, consisted of T and B cells, and macrophages (microglia), associated with nerve cells necrosis and neuronophagia in regions of viral replication. Residual lesions are characterized by loss of neurons and microglial scarring. Cerebral and spinal meninges usually show diffuse infiltration with lymphocytes and sometimes neutrophils. The most extensive meningeal inflammation is around the cerebellum [38, 41].
