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 microcephaly3–9, 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 ZIKV10–22. 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. The role of AXL receptor tyrosine kinase during Zika virus infection has been the subject of debate. Here, it is shown to inhibit type I interferon responses elicited by astrocyte infection in a STAT-dependent manner, enabling virus replication.