Researchers uncover how Zika virus causes microcephaly whereas other flaviviruses do not

Zika virus (ZIKV) causes microcephaly, whereas other related pathogenic flaviviruses do not. To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which requires crossing of the placental barrier.

Studies demonstrate that mammalian cell-derived ZIKV, but not two other globally relevant flaviviruses, efficiently infects fetal endothelial cells, a key component of the placental barrier, because only ZIKV can efficiently use the cell-surface receptor AXL.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have uncovered the details behind the virus’s unique ability to cross the placental barrier and expose the fetus to a range of birth defects that often go beyond microcephaly to include eye and joint injury, and even other types of brain damage.

The researchers found that human umbilical endothelial cells, derived from four donors in the study, proved far more susceptible to Zika infection than to other viruses, with viral counts as much as a hundred or thousand times higher than West Nile or dengue virus. The new research also suggests that Zika virus learned to exploit something of a secret passage, a cell surface molecule known as AXL, while West Nile and dengue viruses did not.

“Zika uses AXL to efficiently slip past one of the major barrier cell types in the placenta: fetal endothelial cells, which are the gateway to access fetal circulation,” said Choe.

What may help make the Zika virus particularly infectious in cells that other flaviviruses can't infect, said TSRI Research Associate Audrey Richard, a first author of the study, is that it profits from the built-in function of AXL. “The physiological function of AXL is to quench activated immune reactions, including the antiviral interferon response,” said Richard. “By using AXL, Zika virus catches two birds with one stone; it enters cells and also gains favorable environment for its replication inside the cells.”

Zika is able to take advantage of AXL by binding to an intermediate molecule known as Gas6, which is present in blood and other bodily fluids. Gas6 acts as an active bridge between the virus and AXL by binding AXL on one end and the virus membrane on the other, helping the virus utilize AXL and gain entry to host cells.

These differences may help explain why, among related viruses, only Zika can efficiently access and infect the fetal bloodstream.

“We don’t yet understand why Zika virus uses AXL and the others don’t,” Choe added. “The common belief is that all flaviviruses have similar structures, but our findings suggest that Zika virus may have a different average population structure than others. This has significant scientific and clinical implications.”

“Structural studies show that most of the infectious virion membrane is completely covered with viral proteins, which makes it difficult for Gas6 to bind to the Zika virus membrane underneath the protein shell,” said TSRI Research Associate Byoung-Shik Shim, the study’s other first author. “However, flavivirus particles assume many asymmetric shapes and are in continuous dynamic motion, which likely exposes patches of the virion membrane. Our study suggests that Zika virus exposes enough membrane for Gas6 binding, whereas West Nile and dengue viruses do not.”

The researchers also speculated on Zika virus’ pathology. AXL is also present in the blood-brain barrier, the eye-blood barrier and the testes—where it maintains integrity of the blood vessels and the functions of the testes. It may be used by Zika virus to infect those cells and may explain Zika virus’ ability to infect the fetal brain and eye and to transmit sexually.

Source: The Scripps Research Institute