The importance of AXL receptors as an entry site for Zika virus on nervous system developmental cells.
Introduction: Zika Virus (ZIKV) is a positive strand RNA Flavivirus. It is transmitted by the Aedes mosquito, but also can be transmitted sexually or through breastfeeding. In 2015, a new outbreak of ZIKV in the Americas was linked to microcephaly1. (Alvarado). Microcephaly is a disorder in neurodevelopment that occurs due to abnormal cell proliferation, causing decreased brain size. It is a very serious disease that can lead to intellectual disabilities or more harmful neurological deficits. ZIKV is able to cross the placenta to infect developing cells such as the neural progenitor cells in the fetus, and cause premature cell death2. (wen) In order to development treatment to prevent ZIKV from causing problems in the fetus, it is important to learn how the virus enters developing cells. Studies were performed to find out the importance of the AXL receptor in ZIKV infection of neuroprogenitor and other developmental cells. Methods: Magnetic relaxation-sensitive nanoparticles were used to recognize the interaction between ZIKV and AXL receptors by testing for affinity between the two3. AXL receptors were ablated in fibroblast cells using CRISPR/Cas9, and ZIKV was added to the cells4. Anti-axl antibodies, followed by ZIKV RNA, were added to CHME3 microglial cell line, primary and human murine astrocytes, as well as human progenitor cells to test if AXL receptors were important for viral entry in those cells5. AXL receptor was deleted in stem cells by inserting doxycycline-inducible Cas9 into AAVS1 locus of human pluripotent cells. ZIKV RNA was inserted into both cell types. Cerebral organoids with and without AXL receptor were infected with ZIKV6. Results: AXL receptors showed high affinity to ZIKV3. Fibroblasts with AXL knockouts showed decreased infection by ZIKV4. The AXL antibody added lowered the infection of human and primary astrocytes, and CHME3 cells. However, it did not affect the infection of human neuroprogenitor cells5. AXL knockout and AXL wildtype stem cells both had decreased in viability, and were infected by ZIKV. The cerebral organoid with AXL knockout and AXL wild type cells both showed decrease in size6. Conclusion: AXL receptors were significant for ZIKV entry in fibroblast cells, primary astrocytes, and CHME3 cells. However, they do not play a significant role in ZIKV entry in neuroprogenitor cells. Other routes of entry have to be researched to find an effective method of treatment to prevent microcephaly.
- Alvarado-Socarras JL, Idrovod AJ, Contreras-Garcíae G, et al. Congenital microcephaly: A diagnostic challenge during Zika epidemics. Travel Med and Infectious Disease.
- Wen Z, Song H, Ming G. How does Zika cause microcephaly? Genes and Development. 2017;31(9):849-861.
- Shelby T, Banerjee T, Zegar I, et al. Highly Sensitive, Engineered Magnetic Nanosensors to Investigate the Ambiguous Activity of Zika Virus and Binding Receptors. Sci Rep. 2017;7(1):7377.
- Persaud M, Martinez-Lopz, A, Buffone, C, et al. Infection by Zika viruses require the transmembrane protein AXL, endocytosis and low pH. Virology. 2018;518:301-312.
- Meertens L, Labeau A, Dejarnac O, et al. Axl Mediates Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Rep. 2017;18(2):324-333.
- Wells M, Salick M, Wiskow O, et al. Genetic Ablation of AXL Does Not Protect Human Neural progenitor Cells and Cerebral Organoids from Zika Virus Infection. Cell Stem Cell. 2016;19(6):703-708.