Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):7117-7122. doi: 10.1073/pnas.1719266115. Epub 2018 Jun 18.
Maternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood-brain barrier, thus allowing infection of the brain later in life.
母体 Zika 病毒（ZIKV）感染在妊娠期间被认为是导致人类胎儿小头症和其他神经异常的原因。目前尚不清楚 ZIKV 如何进入胎儿中枢神经系统（CNS）中高度脆弱的神经祖细胞群体，以及中枢神经系统的哪些细胞类型可能是病毒储存库。相比之下，相关的登革热病毒（DENV）不会引起致畸性。为了在体外模拟病毒与胎儿中枢神经系统细胞的相互作用，我们研究了 ZIKV 和 DENV 对不同诱导多能干细胞衍生的人类细胞的趋向性，特别关注类小胶质细胞。我们表明，ZIKV 感染同基因神经祖细胞、星形胶质细胞和类小胶质细胞（pMGLs），但仅对神经祖细胞具有细胞毒性。感染的神经胶质细胞会繁殖 ZIKV 并随着时间的推移维持 ZIKV 载量，导致病毒传播到易感细胞。DENV 引发更强的免疫反应，并且可以更有效地被神经和神经胶质细胞清除。pMGLs 在与神经球体共培养时会侵入组织，并且在感染 ZIKV 时会引发神经感染。由于小胶质细胞来源于靠近母体血管的原始巨噬细胞，因此它们可能充当 ZIKV 的病毒储存库，并建立对胎儿大脑的感染。入侵的小胶质细胞感染不成熟的神经干细胞可能发生在妊娠早期，在脑原基血管生成之前。我们的数据也与 ZIKV 和 DENV 影响血脑屏障的完整性一致，从而允许在生命后期感染大脑。
