Investigation of West Nile Virus Off-Pathway Membrane Fusion Mechanisms using Kinetic Modeling

Abstract

West Nile virus (WNV) is a positive-sense, single-stranded RNA virus that causes febrile illness (West Nile fever) in humans. It is a member of the flavivirus genus, which includes dengue virus, tick-borne encephalitis, yellow fever virus, and Zika virus. To infect a host cell, West Nile virions first bind to the host cell plasma membrane. Upon binding, the virions are taken up via endocytosis, during which a decrease in pH causes the virions to fuse with the endosomal membrane. Fusion is mediated by the viral glycoprotein E, which is triggered by endosomal pH and undergoes a dimer-to-trimer rearrangement during the fusion process. Previously, we and others used simple chemical kinetics modeling and a cellular automaton simulation to show that an off-pathway state is necessary to fit WNV and Zika virus fusion data. Here, we investigate hypotheses to further explore what the off-pathway state entails, including whether the off-pathway state occurs before or after fusion loop insertion, and whether it occurs as a monomer or a multimer state. We also discuss comparisons between the ability of the off-pathway model to fit both West Nile virus and dengue virus fusion data.