Protein on neural stem cells hijacked by Zika virus

Zika attacks human neural stem cells, perhaps because it can hijack a protein on the surface of those cells.

AXL sits on the surface of neural stem cells and binds to stray molecules passing by in its environment. These stray molecules are known as ligands and may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, and yes, even nutrients. Each reacts with the AXL receptor on the cell surface, changing that cell's metabolism and function.

This signal exchange, called ligand binding, allows for communication between a cell and its outside environment. It initiates a chain of reactions which ultimately affects how a gene makes its product — such as protein — in the process known as gene expression.

Researchers at the University of California, San Francisco have found that AXL is abundant on the surface of neural stem cells — but not on neurons in the developing brain. AXL codes for Tyrosine-protein kinase receptor UFO — an enzyme in humans initially designated as UFO for its' unidentified functions.

The research is published in Cell Stem Cell on March 30, 2016.

"While by no means a full explanation, we believe that the expression of AXL by these cell types is an important clue for how the Zika virus is able to produce such devastating cases of microcephaly, and it fits very nicely with the evidence that's available," says senior study author Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. "AXL isn't the only receptor that's been linked with Zika infection, so next we need to move from 'guilt by association' and demonstrate that blocking this specific receptor can prevent infection."

Neural stem cells expressing AXL are only present in the second trimester of pregnancy. Called radial glial cells, they give rise to a variety of cell types (e.g., neurons and astrocytes) helping build the cerebral cortex.

Researchers also found AXL is expressed by stem cells of the retina.

Disruptions in these cell types is consistent with Zika infection symptoms in the fetus: microcephaly, a brain lacking in folds, and eye lesions.

Kriegstein's lab has a long-time interest in brain development. When the Zika outbreak hit, first authors Tomasz Nowakowski and Alex Pollen realized from their previous research that viruses similar to Zika — like Dengue virus — seem to use AXL as a cell entry point leading to infection.

They then analysed gene expression to look for AXL's presence across mouse brain, ferret brain, human stem cell-derived brain organoids, and developing brain tissue in humans. Each of these models revealed that radial glial cells expressed AXL.

They then used antibody trackers in developing tissues and organoids to locate the AXL receptor on neural stem cells. They found that AXL aggregates in areas where neural progenitor cells contact either cerebrospinal fluid or blood vessels. These areas give Zika easy reach to vulnerable host cells.

"We still don't understand why Zika in particular is so virulent to the developing brain," Kriegstein says.

Pending confirmation that Zika is using AXL for neural stem cell entry, Kriegstein's group would next explore if the receptor can be used for therapeutic purposes.

Since the protein is important for neural stem cell proliferation, it is unlikely that blocking AXL in the fetal brain is an option.

But perhaps there's a way to treat women at risk with an AXL inhibitor — to prevent Zika entering the fetus in the first place.

Abstract Highlights:
• Single-cell analysis reveals expression and specificity of candidate Zika receptors
• AXL shows strong expression in human radial glia, brain capillaries, and microglia
• Developing human retina progenitors also show high AXL expression
• AXL expression is conserved in rodents and human cerebral organoid model systems

Summary
The recent outbreak of Zika virus (ZIKV) in Brazil has been linked to substantial increases in fetal abnormalities and microcephaly. However, information about the underlying molecular and cellular mechanisms connecting viral infection to these defects remains limited. In this study we have examined the expression of receptors implicated in cell entry of several enveloped viruses including ZIKV across diverse cell types in the developing brain. Using single-cell RNA-seq and immunohistochemistry, we found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells, and microglia in developing human cortex and by progenitor cells in developing retina. We also show that AXL expression in radial glia is conserved in developing mouse and ferret cortex and in human stem cell-derived cerebral organoids, highlighting multiple experimental systems that could be applied to study mechanisms of ZIKV infectivity and effects on brain development.

Cell Stem Cell, Nowakowski et al.: "Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor" http://dx.doi.org/10.1016/j.stem.2016.03.012 

This research was supported by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.

The Cell Press family of journals is committed to ensuring that the global response to public health emergencies is informed by the best available research evidence and data, and as such, we will make all content concerning the Zika virus free to access. We will work in partnership with reviewers to fast-track review all submissions concerning Zika. We will adapt the editorial criteria that we apply to Zika submissions by asking reviewers to evaluate only if the research methods are sound and support the conclusions and if the work will contribute in some way toward resolving the immediate challenges. We will expedite publication of papers that meet these two criteria.

Cell Stem Cell (@CellStemCell), published by Cell Press, is a monthly journal that publishes research reports describing novel results of unusual significance in all areas of stem cell research. Each issue also contains a wide variety of review and analysis articles covering topics relevant to stem cell research ranging from basic biological advances to ethical, policy, and funding issues. Visit: http://www.cell.com/cell-stem-cell. To receive Cell Press media alerts, contact press@cell.com

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A section through a stem cell-derived cerebral organoid (mini-brain in a dish) where
radial glia stem cells are RED, neurons (BLUE), and the AXL receptors are GREEN.
Image Credit: Elizabeth Di Lullo, Department of Neurology, University of California,
San Francisco, CA, USA