Comparative analysis of the signaling dynamics and therapeutic responses during infection of West Nile virus by in silico approaches.

Abstract

West Nile Virus is a neurotropic virus that is now considered as the leading agent behind West Nile fever and encephalitis. It was primarily isolated from a patient in UGANDA (1937) and since then it has caused numerous outbreaks in various regions of the world. Still no vaccine has been approved yet for the treatment of West Nile Virus (WNV) infection in humans. Only supportive care can be provided to treat patients. Innate immune system provides primary line of defense against viral pathogens and connect innate immunity with adaptive immunity. Massive progress has been made in recent years to understand innate immune response induced by viruses, because most of the pathogenic infections can be controlled at the level of innate immunity. In case of WNV, it has been found that innate immune responses are critical to control its infection. WNV attacking host cells are initially detected by specialized host cell receptors encoded by cells of germ line known as Pattern Recognition Receptors that initiate the host innate immune responses against viral infection. In the current study, extended Systems Pharmacology model of WNV infection comprising of Toll Like Receptors (TLRs) 3 and 7, RIG-1/MDA5 receptors and JAK-STAT mediated signaling pathways was developed using quantitative approach of systems biology. The model can help to understand host-viral interactions, evasion of WNV from innate immunity and most importantly to study the effects of FDA approved drugs along with the prediction of novel therapeutic targets. Network and sensitivity analysis along with the simulation of model identified that such drugs that can target viral entities or enhance the induction of anti-viral host responses can significantly reduce WNV titer. So, the efficacy of FDA approved drugs like Ribavirin, IFN-α-2b and Sofosbuvir was determined in the WNV mediated signaling pathway. The drug Sofosbuvir was found to be highly effective as it significantly reduces WNV levels with lesser concentration in reduce time course compared to that of Ribavirin and IFN-α-2b. Therefore, the effect of Sofosbuvir should be analyzed against WNV iv Abstract in wet lab experiments as it can emerge as a potential candidate not only against WNV but also against other flaviruses.