Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Division of Academic Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK; Division of Academic Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
Neuron. 2022 Dec 7;110(23):3936-3951.e10. doi: 10.1016/j.neuron.2022.09.002. Epub 2022 Sep 28.
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 (IFNβ) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNβ treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies.
寨卡病毒（ZIKV）可感染人类发育中的大脑（HDB）祖细胞，导致流行的小头畸形，而类似的细胞趋向性为成人大脑癌症——胶质母细胞瘤（GBM）提供了治疗潜力。我们比较了含有 SOX2+神经祖细胞的 HDB 和 GBM 原代组织外植体中的有效 ZIKV 感染。引人注目的是，尽管 HDB 被证明对 ZIKV 感染普遍易感，但 GBM 更具抗性，这与先天免疫表达特征相关。事实上，GBM 衍生的 CD11b+小胶质细胞/巨噬细胞是保护祖细胞免受 ZIKV 感染的必需和充分条件，以非细胞自主的方式。使用 SOX2+GBM 细胞系，我们发现含有 I 型干扰素 β（IFNβ）的 CD11b+条件培养基促进了祖细胞对 ZIKV 的抗性，而 JAK1/2 信号通路的抑制则恢复了有效的感染。此外，CD11b+条件培养基和 IFNβ 处理使 HDB 祖细胞系和外植体对 ZIKV 产生抗性。这些发现为 HDB 祖细胞的神经保护以及增强的 GBM 溶瘤治疗提供了深入了解。
