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AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling


Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain–Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3,4,5,6,7,8,9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10,11,12,13,14,15,16,17,18,19,20,21,22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.

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This work was supported by the National Science Foundation of China (81430030 to J.X.), the ShanghaiTech University Startup Fund (to B.J. and J.L.), the Shanghai Public Health Clinical Center (to X.Z.), the Developmental Center of Shanghai Shenkang Hospital (SHDC12014104 to X.Z.) and the Shanghai Advanced Biosafety and Pathogen Diagnostic Platform (15DZ2290200 to X.Z.).

Author information

J.X. and J.L. conceived this study. Jian C., Y.-F.Y., B.J., X.Z., J.L. and J.X. designed the experiments. Jian C., Y.-F.Y., Y.Y., Yongquan H., S.-L.S., Y.-R.C., R.B., Y.-J.L. and J.L. performed the experiments. P.Z., Yunwen H. and L.L. prepared the ZIKV. Jun C. analysed the RNA-Seq data. Jian C., Y.-F.Y., J.L. and J.X. prepared the manuscript.

Competing interests

The authors declare that they have no competing financial interests.

Correspondence to Xiaoyan Zhang or Jia Liu or Jianqing Xu.

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Fig. 1: AXL knockout prevents productive ZIKV infection in human astrocytes.
Fig. 2: AXL knockout does not block ZIKV entry but protects astrocytes via an IFNAR signalling-dependent mechanism.
Fig. 3: AXL antagonizes type I IFN signalling during ZIKV infection via an SOCS1-dependent mechanism.
Fig. 4: Mechanism of AXL-SOCS1 negative regulation of type I IFN signalling.