Variation in virion phosphatidylserine content drives differential GAS6 binding among closely related flaviviruses

Among flaviviruses, Zika virus uniquely causes microcephaly and congenital defects. While no flavivirus-specific entry receptors have been identified, they commonly take advantage of phosphatidylserine (PS) receptors to enter cells. Our previous studies revealed that Zika virus uniquely utilizes AXL, found in immune-privileged sites, such as the brain and placenta, via binding to its ligand, GAS6. Our current study shows that despite being produced from the same cells, the Zika virus has substantially higher PS content than closely related dengue and West Nile viruses, which likely explains the Zika virus's unique ability to bind GAS6. These findings provide insight into how closely related flaviviruses can vary substantially in their use of cellular entry factors, potentially contributing to the distinct diseases they cause.