AXL Promotes Zika Virus Infection in Astrocytes by Antagonizing Type I Interferon Signaling Pathway

Abstract Zika virus (ZIKV) is known to be associated with neonate microcephaly and Guillain-Barré syndrome in human adults. Despite the progress on understanding the causal link between ZIKV infection and microcephaly, the life cycle and pathogenesis of ZIKV remains elusive. In particular, recent studies have revealed a controversial role of AXL, a TAM family kinase receptor previously deemed as the entry receptor of ZIKV. In this study, we show that though genetic ablation of AXL protects primary human astrocytes and U-251MG astrocytoma cells from ZIKV infection, AXL knockout (KO) does not block the entry of ZIKV, instead it facilitates the up-regulation of type I interferon (IFN) signaling genes, including interferon regulatory factor 7 (IRF7), a key interferon transcriptional factor, and a number of type I interferon and interferon stimulating genes (ISGs). Knockout of type I IFN receptor a chain (IFNAR1) rescues the vulnerability of AXL KO astrocytes to ZIKV infection. In addition, AXL KO in astrocytes results in the down-regulation of SOCS1 in primary astrocytes and the failure to retain the homeostasis of SOCS1 in astrocyte cell lines, a known inhibitor of type I IFN signaling pathway, thus revealing important roles of AXL in maintaining the homeostasis of SOCS1 and thereby in containing type I interferon signaling pathway. Taken together, our study demonstrates that AXL does not function as the sole, if at all, entry receptor of ZIKV, but instead promotes ZIKV infection in astrocytes by SOCS1-mediated antagonism of type I interferon (IFN) signaling.