Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and human neural cells

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNb) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNb treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuropro-tection for HDB progenitors as well as enhanced GBM oncolytic therapies.

Automated summary

Zika virus can infect human developing brain progenitors, leading to epidemic microcephaly, but it has limited infectivity for adult brain cancer glioblastoma. CD11b+ microglia/macrophages derived from glioblastoma are able to protect progenitors against Zika virus infection in a non-cell autonomous manner. Treatment with interferon beta and inhibition of JAK1/2 signaling can enhance the resistance of progenitors to Zika virus. These findings have important implications for neuroprotection and improved treatment of brain cancer.