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

Nat Microbiol. 2018 Mar;3(3):302-309. doi: 10.1038/s41564-017-0092-4.

Jian Chen ¹, Yi-Feng Yang ², Yu Yang ¹, Peng Zou ¹, Jun Chen ³, Yongquan He ¹, Sai-Lan Shui ², Yan-Ru Cui ², Ru Bai ¹, Ya-Jun Liang ², Yunwen Hu ¹, Biao Jiang ², Lu Lu ¹, Xiaoyan Zhang ⁴ ⁵, Jia Liu ⁶, Jianqing Xu ⁷ ⁸

Affiliations

1 Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China.
2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
3 Department of Ecology and Genetics, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
4 Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China. zhangxiaoyan@shaphc.org.cn.
5 State Key Laboratory for Infectious Disease Prevention and Control, China Centers for Disease Control and Prevention, Beijing, China. zhangxiaoyan@shaphc.org.cn.
6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. liujia@shanghaitech.edu.cn.
7 Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai, China. xujianqing@shaphc.org.cn.
8 State Key Laboratory for Infectious Disease Prevention and Control, China Centers for Disease Control and Prevention, Beijing, China. xujianqing@shaphc.org.cn.

PMID: 29379210 DOI: 10.1038/s41564-017-0092-4

Abstract

Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barré syndrome^1,2. While progress has been made in understanding the causal link between ZIKV Infection and microcephaly^3-9, 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 ZIKV^10-22. 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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