New findings suggest how Zika virus crosses the placental barrier

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Researchers from the Scripps Research Institute (CA, USA) have uncovered a mechanism that allows Zika virus to cross the placental barrier and enter the fetal bloodstream, providing an insight into the unique ability of the virus to cause microcephaly and other congenital complications.

Zika has caused international concern due to its ability to cause birth defects. This requires the virus to overcome a substantial obstacle; crossing the placental barrier. However, to date researchers have not been able to pinpoint how Zika crosses this barrier and why other closely related viruses cannot.

In this study, published recently in the Proceedings of the National Academy of Sciences, the researchers compared Zika with two other flaviviruses, West Nile virus (WNV) and dengue. They examined human umbilical vein endothelial cells and observed that these cells were far more susceptible to Zika infection compared with the other flaviviruses. Viral titers for Zika-infected cells were approximately 100- or 1000-fold higher than those from WNV or dengue, respectively.

The team demonstrated that the Zika virus utilized a host cell surface receptor termed AXL, a receptor tyrosine kinase, to enter the human umbilical vein endothelial cells. Moreover, Zika does this with much greater efficiency than both dengue and WNV.

The group also discovered that Zika virus takes advantage of AXL by binding its ligand, a protein termed Gas6. They suggested that this interaction allowed the virus to bypass fetal endothelial cells gaining access to fetal circulation and other tissues.

Co-first author Audrey Richard, from the Scripps Research Institute, explained: “The physiological function of AXL is to quench activated immune reactions, including the antiviral interferon response. 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.”

The study’s other co-first author, Byoung-Shik Shim (Scripps Research Institute) added: “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.

“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.”

This study is the first to demonstrate that Zika utilizes AXL to enter the fetal bloodstream, providing an insight into some of the congenital complications caused by the virus. The AXL molecule is also present in the blood–brain barrier, eye–blood barrier and testes; this may explain some of the pathology of Zika, for example, its ability to infect the fetal brain and to be sexually transmitted.

Lead author Hyeryun Choe (Scripps Research Institute) concluded: “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.”

Sources: Richard AS, Shum B Kwon Y et al. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. PNAS. doi:10.1073/pnas (2017) (Epub ahead of print); www.scripps.edu/news/press/2017/20170206choe.html

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