The overall aim of ASKLEPIOS is to unravel and increase our understanding of the mechanisms that govern pathogenesis of rabies virus (RABV) infection, in pursuit of the rational identification of novel therapeutic leads for rabies encephalitis. Several studies have been conducted over the past decades attempting to unravel the pathogenesis of this deadly disease, however with limited success. New knowledge on the mechanisms of the RABV life-cycle and interaction with the host is needed to identifying clinically applicable therapeutic leads, in search of rational intervention strategies. The project objectives are to:1. Identify molecules that inhibit RABV replication2. Identify molecules that inhibit detrimental host responses to RABV infection:3. Show whether opening the blood-brain-barrier (BBB) improves treatment efficacy:4. Validate the potential of the molecules identified under 1 and 2 to be used as post-exposure prophylaxis (PEP) when classical PEP is ineffective.In pursuit of these objectives ASKLEPIOS will perform in vitro screening of the anti-viral effect of type-I IFNs, MAP kinase inhibitors and siRNAs. Second, the therapeutic potential of inhibiting the pyroptotic pathway and inflammatory response will be investigated by using inhibitors of caspase-1, IL-1β, TNF-α IL-6 and MAP kinases. Third, the capacity of molecules to reach the brain will be first evaluated using an efficient in vitro BBB system and in vivo mouse studies.. The most efficient molecule to open the BBB will be co-administrated with the selected therapeutic molecules in the subsequent stages of the project. The results will be collected and synthesized and tested in mice to identify the most effective approach. The ability to clear infection and recover from rabies will be evaluated for each therapeutic scheme identified