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.
