John Williams

 Introduction: Study of the outbreak of Zika in Brazil in 2015 showed that the prevalence of microcephaly increased from 0.6 per 10,000 live births in states without confirmed Zika cases to 2.8 per 10,000 live births in states with confirmed cases.[1] These epidemiological data were confirmed in the laboratory when immature neuroblastoma cells were shown to be susceptible to infection by Zika virus.[2] The next step in understanding this virus is determining the mechanism of damage to the nervous system. The TAM receptor AXL shows promise as a possible binding site for Zika in the developing human cortex. Methods: Immunohistochemistry was used to study the expression of AXL in the developing cortex.[3] High AXL expressing cells were subjected to infection with Zika and were compared to the murine microglial cells that have low AXL expression. The percentage of infected cells was found 24 hours later with flow cytometry. A similar experiment was performed in which CRISPR Cas9 was used to create AXL knockouts of CHME3 and assess their susceptibility to Zika infection. Transduction of wild type AXL cDNA was used to restore the knockout cells’ AXL and determine if Zika susceptibility would return.[4] Results: AXL was found to be highly expressed in radial glia apical end-feet and at the pial end-feet of radial glia near the meninges. The high AXL expressing cell lines were found to be susceptible to productive infection by Zika, while the murine microglial cells were resistant to infection. The AXL knockout cell line were found to be resistant to Zika infection, while the restored CHME3 line were susceptible to infection. Conclusions: The expression patterns of AXL in radial glia end feet suggest a means for infection of radial glial cells via CSF or blood. Radial glial cell infection would be extremely detrimental due to their function as progenitor for many different cell types in the developing cortex. Inhibition of AXL is a promising candidate for prevention of nervous system damage by Zika, but also has drawbacks. AXL serves an important role in neural stem cell survival, proliferation, and neurogenesis. AXL also serves to maintain the blood brain barrier. Blockage of the protein altogether would cause more detrimental effects than positive. More research is needed to determine the role of other factors such as TYRO3 and Gas6 to further understand the mechanism of nervous system damage to find a safe and effective vaccine.

1. Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, et al. Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy – Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65(9):242-7 doi: 10.15585/mmwr.mm6509e2[published Online First: Epub Date]|.
2. Hughes BW, Addanki KC, Sriskanda AN, McLean E, Bagasra O. Infectivity of Immature Neurons to Zika Virus: A Link to Congenital Zika Syndrome. EBioMedicine 2016;10:65-70 doi: 10.1016/j.ebiom.2016.06.026[published Online First: Epub Date]|.
3. Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells. Cell Stem Cell 2016;18(5):591-6 doi: 10.1016/j.stem.2016.03.012[published Online First: Epub Date]|.
4. Meertens L, Labeau A, Dejarnac O, et al. Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Rep 2017;18(2):324-33 doi: 10.1016/j.celrep.2016.12.045[published Online First: Epub Date]|.