Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses

Meertens, et al.

Cell reports. 2017;18:324-333

Speaker: Yun-Erh Chuang (莊筠兒)                 Time: 13:10~14:00, Dec 6, 2017                     

Commentator: Dr. Chun-Hsien Chu (朱俊憲老師)    Place: Room 601                                         

Abstract

ZIKV is associated with several neurological disorders, such as Guillain-Barré syndrome, moreover, it may cause congenital microcephaly and abortion after infection during pregnancy. However, the mechanisms of ZIKV neurotropism are poorly understood. Axl is express in microglial cells and astrocytes in human developing brain, it belongs to the Tyro3 Axl Mer (TAM) family, a group of tyrosine kinase receptors involved in the clearance of apoptotic cells and regulation of innate immunity. The TAM ligands Gas6 and protein S (ProS) recognize the PtdSer expressed on apoptotic cells, being a bridging molecule via their N-terminal Gla domain.¹ Previous studies have shown that dengue virus can bind indirectly to Axl through Gas6, and utilizing the mechanism mentioned before to entry target cells.² Therefore, the authors postulated that ZIKV use the same mechanism to entry human glial cells (astrocytes and microglia). In order to investigate the relationship between ZIKV and Axl receptor, the authors explored the Axl expression of ZIKV-infected cells and its ligands. They found that ZIKV-infected CHME3 microglial cell line and primary human astrocytes expressed high levels of Axl and the Axl-mediated ZIKV infection is mainly dependent on the TAM ligands Gas6. Furthermore, they explored the endocytic route that ZIKV utilize to entry the Axl-expressing cells and the role of Axl kinase activities in innate immune responses. The results indicated that ZIKV use clathrin-mediated endocytosis pathway to entry the Axl-expressing cells and the Axl may enchance the ZIKV infection. Moreover, there are two inhibitors, engineered Axl decoy receptor---MYD1 and the kinase inhibitor ---R428, which may display antiviral activity. In conclusion, ZIKV entry human glial cells through the bridge of Axl and Gas6 and regulate the innate immune responses.

Reference

1.       Lemke, G. and Rothlin, C.V. Immunobiology of the TAM receptors. Nat.Rev.Immunol 8, 327–336 (2008).

2.       Meertens, et al. The TIM and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus Entry. Cell Host & Microbe 12, 544–557 (2012).