Rabies implicated signaling network; from static to dynamic modelling

Rabies is a member of the Rhabdoviridae family that causes lethal encephalitis. The lethality mechanism, as well as related psychological symptoms, have still remained a mystery. The mechanistic view based on signaling networks would be expected to disclose events that occur in the late stage of rabies. Aims: In this study, a systems biomedicine approach was undertaken to identify the implicated signaling network in rabies. This was started by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. Then, the Boolean model was reconstructed to simulate the dynamic behavior of the model and predict potential drug target in order to block Rabies propagation within infected neuron cells. Results: By means of unifying mRNA and microRNA detected integrated differentially expressed genes and reconstructing a refined protein–protein interaction network, the rabies-implicated signal transduction network (RISN) was extracted and elaborated. The RISN was categorized into three parts namely; (1) interferon circumvent, (2) toward proliferation and survival, and (3) neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection. The second part was selected to implement dynamic logical modeling. The results indicated some desired steady states which are accessible by changing trajectories by means of drug targeting. To validate findings, differential expression of genes, viral titration assay, cell- and caspase-based apoptosis rate test was conducted before and after inhibition of predicted targets.