Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents the most important flaviviral neural infection in Europe and north-eastern Asia. In the central nervous system (CNS), neurons are the primary target for TBEV infection; however, infection of non-neuronal CNS cells, such as astrocytes, is not well understood. In this study, we investigated the interaction between TBEV and primary human astrocytes. We report for the first time, to the best of our knowledge, that primary human astrocytes are sensitive to TBEV infection, although the infection did not affect their viability. The infection induced a marked increase in the expression of glial fibrillary acidic protein, a marker of astrocyte activation. In addition, expression of matrix metalloproteinase 9 and several key pro-inflammatory cytokines/chemokines (e.g. tumour necrosis factor α, interferon α, interleukin (IL)-1β, IL-6, IL-8, interferon γ-induced protein 10, macrophage inflammatory protein, but not monocyte chemotactic protein 1) was upregulated. Moreover, we present a detailed description of morphological changes in TBEV-infected cells, as investigated using three-dimensional electron tomography. Several novel ultrastructural changes were observed, including the formation of unique tubule-like structures of 17.9 ±0.15 nm diameter with associated viral particles and/or virus-induced vesicles and located in the rough endoplasmic reticulum of the TBEV-infected cells. This is the first demonstration that TBEV infection activates primary human astrocytes. The infected astrocytes might be a potential source of pro-inflammatory cytokines in the TBEV-infected brain, and might contribute to the TBEV-induced neurotoxicity and blood-brain barrier breakdown that occurs during TBE. The neuropathological significance of our observations is also discussed.

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

Institute of Parasitology Biology Centre of the Academy of Sciences of the Czech Republic Branišovská 31 CZ 37005 České Budějovice Czech Republic Faculty of Science University of South Bohemia Branišovská 31 CZ 37005 České Budějovice Czech Republic

Institute of Parasitology Biology Centre of the Academy of Sciences of the Czech Republic Branišovská 31 CZ 37005 České Budějovice Czech Republic Faculty of Science University of South Bohemia Branišovská 31 CZ 37005 České Budějovice Czech Republic Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic

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