Abstract
Neurotropic tick borne encephalitis virus (TBEV) causes life-threatening disease, and accounts for most cases of tick-transmitted viral infections in Central and Eastern Europe and Russia. No specific treatment for TBEV infections exists, and vaccination is recommended for people at risk. So far, various nucleoside analogues have been investigated in vitro as potential candidates for treatment of TBEV infections. However, in vitro experiments with more complex cell culture systems, such as organotypic culture slices which model the sophisticated architecture of the target tissue are lacking. Using TBEV as a model, we investigated the suitability of rat organotypic cerebellum slices (OCS) to study the effectiveness of nucleoside analogues with a well-known anti-TBEV activity. In these OCS, 50 μM of the nucleoside analogues 2’-C-methyladenosine (2’-CMA) and especially 7-deaza-2’-C-methyladenosine (7-deaza-2’-CMA) exhibited strong inhibitory effects on TBEV replication, reducing viral titers to an average of 103-fold and TBEV RNA content 60-90-fold. In contrast, the influence of 2’-C-methylcytidine (2’-CMC) on TBEV replication was very weak, reducing virus titers by 10-fold and TBEV RNA content by 3-fold. In agreement with other studies, there was no noticeable difference in TBEV titers between OCS treated with 50 μM of Ribavirin and the DMSO treated controls. All tested nucleoside analogues exhibited excellent cytotoxicity profiles at concentrations of 50 μM. Our findings in OCS were highly comparable to data obtained in cell line culture systems. Therefore, OCS represent an ideal in vitro approach to study antivirals against TBEV and possibly other neurotropic viruses.
Highlights
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a single stranded positive sense RNA virus with a genome of about 11 kb in length
Four nucleoside analogues were investigated for their inhibitory effect on the replication of TBEV strain Hypr in rat organotypic cerebellum slices (OCS)
OCS have the advantage of comprising the entire cell community with the conserved natural structure occurring in the cerebellum of suckling Wistar rats
Summary
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a single stranded positive sense RNA virus with a genome of about 11 kb in length. It expresses a single polyprotein, which is post-translationally cleaved into 3 structural and 7 nonstructural proteins [1]. The principal vectors of TBEV are ticks, belonging to the Ixodidae family, Ixodes ricinus in Central Europe and Ixodes persulcatus in Eastern Europe and Russia [2].
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