Why neural stem cells may be vulnerable to Zika infection

Zika's hypothesized attraction to human neural stem cells may come from its ability to hijack a protein found on the surface of these cells, using it as an entryway to infection. In Cell Stem Cell researchers at the University of California, San Francisco show that the AXL surface receptor, normally involved in cell division, is highly abundant on the surface of neural stem cells, but not on neurons in the developing brain.

The neural stem cells that express AXL are only present during the second trimester of pregnancy. These cells, called radial glial cells, give rise to the variety of cell types (e.g., neurons and astrocytes) that help build the cerebral cortex. The researchers also found AXL expressed by the stem cells of the retina. Disruption of this range of cell types is consistent with the multiple symptoms associated with Zika infection in the developing fetus--including microcephaly, a brain lacking in folds, and eye lesions.

Researchers then used gene expression analysis (single-cell RNA sequencing) to look for AXL's presence across different cell types in mouse brain, ferret brain, human stem cell-derived brain organoids, and developing brain tissue in humans. Each of the models showed expression of AXL by the radial glial cells.

The researchers then used antibody trackers (immunohistochemistry) in the developing tissues and organoids to find out where the AXL receptor was most likely to be found on the neural stem cells. They found that AXL aggregates toward areas where the neural progenitors come into contact with either cerebrospinal fluid or blood vessels. This unique position would give a virus such as Zika an easy way to reach a vulnerable population of host cells.

Pending confirmation that Zika is using AXL for neural stem cell entry, the group is interested in exploring if the receptor could be exploited for therapeutic purposes. Since the protein is important for neural stem cell proliferation, it is unlikely that blocking AXL will be an option in the fetal brain. But perhaps there's a way to treat women at risk with an AXL inhibitor to stop Zika getting into the developing fetus in the first place.