Key Cell-Surface Receptor May Be Gateway for Zika Virus Infection in Utero

The relationship between Zika virus and microcephaly has been well-documented, but why the mosquito-borne disease causes the birth defect in children born to infected pregnant women, when no such complications have been observed in cases of similar vector-borne viruses such as Dengue and West Nile, remains unknown.

However, new research funded by the National Institutes of Health and the state of Florida, ground zero for Zika in the United States, published February 6th in the journal the Proceedings of the National Academy of Sciences seems to go a long way to answering some of the lingering questions regarding this troubling complication, which has been associated with neurologic functioning problems in affected newborns. Researchers identified a potential role for the receptor tyrosine kinase AXL in its development. Interestingly, other viruses linked with the Aedes aegypti mosquito, Dengue and West Nile, do not “efficiently” use AXL as a cell surface receptor to infect fetal endothelial cells that make up a key component of the placental barrier. Chikungunya, which is also linked to the Aedes aegypti mosquito was not included, the authors told Contagion^®, because it is “genetically, serologically, and structurally different” from the other viruses.

Hyeryun Choe, PhD, who lead the research team from The Scripps Research Institute, and Washington University School of Medicine in St. Louis, both of which have been at the forefront of Zika-related research, said in a statement released with the study’s publication, “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. We don’t yet understand why Zika virus uses AXL and the others don’t. 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.” In separate comments made to Contagion^®, Dr. Choe added, “We learned what part of Zika virus one should attack to prevent its infection of the placenta.”

Using human umbilical endothelial cells collected from four donors, Dr. Choe and colleagues found that these cells are significantly more susceptible to Zika infection than they are to infection with the other flaviviruses. Indeed, cells in the study had Zika viral counts up to 1,000-times higher than those of Dengue or West Nile. They believe Zika is able to use AXL by binding to an intermediate molecule called Gas6, which is found in blood, semen, and other bodily fluids. The intermediate molecule also binds to AXL, effectively connecting the virus with the receptor tyrosine kinase, which allows it to enter host cells. Unlike Dengue and West Nile, the authors theorize that Zika exposes sufficient viral membrane to bind to Gas6 and, ultimately AXL. This is vital because AXL is found in the blood-brain barrier, the eye-blood barrier, and the testes, and it may be used by the Zika virus to infect those cells, thus explaining the virus’ ability to infect the fetal brain as well as its sexual transmission. According to Dr. Choe, follow-up studies by the same group will seek to explore the differences between the 3 viruses “more deeply at the molecular level.”

“The physiological function of AXL is to quench activated immune reactions, including the antiviral interferon response,” another study co-author, Audrey Richard, PhD, a microbiologist at Scripps said in the statement, which was issued by Scripps. “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.”

To date, according to the Centers for Disease Control and Prevention (CDC), more than 1,300 pregnant women across the country have been infected with Zika. In all, the CDC reports, 38 babies the United States have been born with virus-related birth defects.

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.