Title : Investigating fusion loop modifications as a strategy to limit flavivirus neuroinvasion
Abstract:
Flaviviruses such as Zika and Powassan virus can cause serious neurological disease because they are able to cross protective barriers in the body including the blood brain barrier and the placenta. This allows the virus to infect the brain and developing fetus, leading to conditions such as microcephaly and encephalitis. While previous studies have explored how viral proteins interact with host cells, the specific structural features that control barrier penetration are still not fully understood. The goal of this project was to investigate how small changes in the flavivirus envelope protein affect receptor binding and transport across a model blood brain barrier.
Envelope protein sequences were analyzed using bioinformatics tools to identify conserved regions involved in membrane fusion. Based on this analysis, three modified envelope variants with targeted amino acid substitutions were designed and modeled using structural prediction software. Molecular docking and molecular dynamics simulations were performed to estimate receptor binding strength and structural stability. The variants were then evaluated using simulated mammalian cell uptake and a transwell based in vitro blood brain barrier model to compare transport efficiency.
Results showed that one modified variant demonstrated a 26 percent reduction in predicted receptor binding strength and a 33 percent decrease in simulated barrier transport compared to the wild type protein. Structural modeling suggested that mutations within the fusion loop disrupted conformational changes needed for membrane fusion. Additionally, cell uptake simulations indicated a 38 percent reduction in viral entry signals for the most effective variant.
Overall, this project highlights the importance of fusion loop residues in enabling flavivirus barrier penetration and demonstrates that targeted envelope modifications can reduce predicted viral entry and transport. These findings provide insight into viral neuroinvasion mechanisms and suggest potential strategies for attenuated vaccine design or therapeutic targeting. Future work will involve experimental validation of envelope variants and expansion to placental barrier models to better understand fetal infection risk.
