On the modelling and analysis of the regulatory network of dengue virus pathogenesis and clearance

[Display omitted] •We used generalized logical approach introduced by Rene Thomas to study TLR3 mediated signaling pathway in dengue virus infection.•We implement kinetic formalism of Rene Thomas along with Model Checking approaches to provide qualitative thresholds of entities in TLR3 associated Biological Regulatory Network of dengue virus, satisfying the biological observations.•Qualitative model was analysed to observe the qualitative behaviours of the model.•We incorporated delays in qualitative model to study the activation and inhibition orders of proteins by hybrid model checking tool HyTech. Dengue virus can ignite both protective and pathogenic responses in human. The pathogenesis is related with modified functioning of our immune system during infection. Pattern recognition receptors like Toll like receptor 3 is vital for the induction of innate immunity in case of Dengue infection. Toll like receptor 3 induces TRIF mediated activation of Type 1 interferons and Fc receptor mediated induction of cytokines. Interferons have been related with clearance of Dengue virus but it has adopted modified regulatory mechanisms to counter this effect. SOCS protein is also induced due to the interferon and cytokine mediated signalling which can subsequently play its part in the regulation of interferon and cytokine production. Our hypothesis in this study relates the pathogenesis of Dengue virus with the SOCS mediated inhibition of our innate immunity. We used the qualitative formalism of René Thomas to model the biological regulatory network of Toll like receptor 3 mediated signalling pathway in an association with pathogenesis of dengue. Logical parameters for the qualitative modelling were inferred using a model checking approach implemented in SMBioNet. A linear hybrid model, parametric linear hybrid automaton, was constructed to incorporate the activation and inhibition time delays in the qualitative model. The qualitative model captured all the possible expression dynamics of the proteins in the form of paths, some of which were observed as abstract cycles (representing homoeostasis) and diverging paths towards stable states. The analysis of the qualitative model highlighted the importance of SOCS protein in elevating propagation of dengue virus through inhibition of type 1 interferons. Detailed qualitative analysis of regulatory network endorses our hypothesis that elevated levels of cytokine subsequently induce SOCS expression which in turn results int