β-catenin restricts Zika virus internalization into human astrocytes by downregulating Axl

Recent outbreak of ZIKV in the Americas have been associated with significant neurologic complications, including microcephaly of newborns. Human fetal astrocytes (HFA) are infected by ZIKV, yet pathways and mechanisms that may regulate ZIKV internalization are not clearly understood. We evaluated the effect of the central mediator of canonical Wnt signaling (-catenin) on ZIKV infection due to its emerging significance in regulation of a number of viruses. We show that -catenin regulates Axl, a receptor for ZIKV in HFAs, at the transcriptional level. Further, ZIKV inhibited -catenin, potentially as a mechanism to overcome its restriction of ZIKV internalization through regulation of Axl. This was evident with three ZIKV strains tested but not with a laboratory adapted strain which has a large deletion in its envelope gene. Finally, we show that -catenin mediated Axl dependent internalization of ZIKV may be of increased importance for brain cells, as it regulated ZIKV infection of astrocytes and human brain microvascular cells, but not kidney epithelial (Vero) cells. Collectively our studies reveal a novel pathway for ZIKV infection of astrocytes, which may inform therapeutic intervention for ZIKV infection of astrocytes. In the data Zika strains were named differently than in the paper 1843 or 43 is PRVABC59, 1844 or 44 is FLR, 76 is MR766, and 39 is IBH36056.