Zika Virus Infection Induces Cranial Neural Crest Cells to Produce Cytokines at Levels Detrimental for Neurogenesis

Zika virus (ZIKV) infection during pregnancy is linked to microcephaly, which is attributed to infection of developing brain structures. ZIKV infects neural progenitor cells in vitro, though its effects on other developmentally relevant stem cell populations, including cranial neural crest cells (CNCCs), have not been assessed. CNCCs give rise to most cranial bones and exert paracrine effects on the developing brain. Here, we report that CNCCs are productively infected by ZIKV, but not by the related dengue virus. ZIKV-infected CNCCs undergo limited apoptosis but secrete cytokines that promote death and drive aberrant differentiation of neural progenitor cultures. Addition of two such cytokines, LIF or VEGF, at levels comparable to those secreted by ZIKV-infected CNCCs is sufficient to recapitulate premature neuronal differentiation and apoptotic death of neural progenitors. Thus, our results suggest that CNCC infection by ZIKV may contribute to associated embryopathies through signaling crosstalk between developing face and brain structures. [Display omitted] •Zika virus, but not dengue, productively infects cranial neural crest cells (CNCCs)•Neurospheres co-cultured with ZIKV-infected CNCCs display altered morphology•ZIKV infection drives CNCCs to secrete elevated levels of neurodevelopmental cytokines•The cytokines LIF and VEGF are sufficient to trigger premature neuronal differentiation Cranial neural crest cells are direct progenitors of the bones and cartilage of the skull and influence central brain development through paracrine secretions. Bayless, Greenberg et al. demonstrate that Zika virus (ZIKV) productively infects cranial neural crest cells, driving cytokine secretion that leads to aberrant neural development in vitro.