Mechanism of Nervous System Damage Caused by ZIKA Virus: The Role of AXL Receptor in Viral Entry
Introduction: Zika virus (ZIKV) is a RNA flavivirus that has gained global attention since 2015 after a major outbreak in Brazil.1-3 Although ZIKV is primarily spread by bites of Aedes mosquitos, it can also be spread through unprotected sexual intercourse as well as through placental transmission from an infected mother.1-4 There are currently no vaccines or specific anti-virals developed to combat ZIKV infections.3 The association of ZIKV with severe neurological disorders such as microcephaly in infants and Guillain-Barre syndrome in adults highlights ZIKV as a global health emergency that needs immediate treatment solutions to prevent permanent disabilities in infected patients.1,4 Currently there is a lot of research about ZIKV with many active clinical trials in planning and development stages. Some of the research has looked into entry factors utilized by ZIKV, which has revealed the major role of the TAM receptor AXL in viral entry.5-9 AXL binds ZIKV through Gas6 and promotes ZIKV infection of many different cell types.7,8,10 Methods: Human microglial cell line (CHME3), human primary astrocytes, human neural progenitor cells (hNPCs) were incubated with anti-AXL polyclonal antibody and small interfering RNA (siRNA).6,8 Another experiment was performed in which CHME3 cells were infected with ZIKV in the absence of fetal calf serum, which naturally contains TAM ligands.8 CHME3 cells and primary astrocytes were also incubated with MYD1 and then infected with ZIKV. MYD1 is an engineered AXL decoy receptor that binds Gas6 and neutralizes it.8 Results: ZIKV infection of human primary astrocytes and CHME3 cells was significantly reduced when incubated with an anti-AXL polyclonal antibody as well as by the siRNA which serves to inhibit AXL expression.6,8 In the absence of TAM ligands, ZIKV infection was dramatically decreased and the addition of Gas6 restored ZIKV infection at levels that were comparable to control cells.8 MYD1 was found to inhibit ZIKV in a dose-dependent manner and inhibited ZIKV binding to CHME3 cells and primary astrocytes.8 Conclusions: Experiments involving Gas6 has suggested a tripartite model of ZIKV entry.7,8,10 Gas6 binds to the phosphatidylserine present on the surface of ZIKV and acts as a bridging molecule to connect ZIKV to AXL.8,10 MYD1 effectively blocks ZIKV infection by sequestering Gas6 and preventing ligand-receptor interaction of Gas6 with AXL.8 The use of MYD1 as a potential ZIKV antiviral is an exciting approach that warrants further research.
- Yun S-I, Lee Y-M. Zika virus: An emerging flavivirus. Journal of Microbiology. 2017;55(3):204-219.
- Song B-H, Yun S-I, Woolley M, Lee Y-M. Zika virus: History, epidemiology, transmission, and clinical presentation. Journal of Neuroimmunology. 2017.
- Sharma A, Lal SK. Zika Virus: Transmission, Detection, Control, and Prevention. Frontiers in Microbiology. 2017;8(110).
- Faizan MI, Abdullah M, Ali S, Naqvi IH, Ahmed A, Parveen S. Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism. Intervirology. 2016;59(3):152-158.
- Retallack H, Di Lullo E, Arias C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proceedings of the National Academy of Sciences. 2016;113(50):14408-14413.
- Hamel R, Dejarnac O, Wichit S, et al. Biology of Zika Virus Infection in Human Skin Cells. Journal of Virology. 2015;89(17):8880-8896.
- Richard AS, Shim BS, Kwon YC, et al. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(8):2024-2029.
- Meertens L, Labeau A, Dejarnac O, et al. Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Reports. 2017;18(2):324-333.
- Nowakowski Tomasz J, Pollen Alex A, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein Arnold R. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells. Cell Stem Cell. 2016;18(5):591-596.
- Lemke G. Biology of the TAM Receptors. Cold Spring Harbor Perspectives in Biology. 2013;5(11).