Comput Biol Chem - On the modelling and analysis of the regulatory network of dengue virus pathogenesis and clearance.


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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 Ren? 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 into the continuous down-regulation of Toll like receptor 3 and interferon. This may result into the Dengue pathogenesis during the stage of immunosuppression. Further analysis with HyTech (HYbrid TECHnology) tool provided us with the real-time constraints (delay constraints) of the proteins involved in the cyclic paths of the regulatory network backing the evidence provided by the qualitative analysis. The HyTech results also suggest that the role of SOCS is vital in homoeostasis.

Resumo Limpo

dengu virus can ignit protect pathogen respons human pathogenesi relat modifi function immun system infect pattern recognit receptor like toll like receptor vital induct innat immun case dengu infect toll like receptor induc trif mediat activ type interferon fc receptor mediat induct cytokin interferon relat clearanc dengu virus adopt modifi regulatori mechan counter effect soc protein also induc due interferon cytokin mediat signal can subsequ play part regul interferon cytokin product hypothesi studi relat pathogenesi dengu virus soc mediat inhibit innat immun use qualit formal ren thoma model biolog regulatori network toll like receptor mediat signal pathway associ pathogenesi dengu logic paramet qualit model infer use model check approach implement smbionet linear hybrid model parametr linear hybrid automaton construct incorpor activ inhibit time delay qualit model qualit model captur possibl express dynam protein form path observ abstract cycl repres homoeostasi diverg path toward stabl state analysi qualit model highlight import soc protein elev propag dengu virus inhibit type interferon detail qualit analysi regulatori network endors hypothesi elev level cytokin subsequ induc soc express turn result continu downregul toll like receptor interferon may result dengu pathogenesi stage immunosuppress analysi hytech hybrid technolog tool provid us realtim constraint delay constraint protein involv cyclic path regulatori network back evid provid qualit analysi hytech result also suggest role soc vital homoeostasi

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