Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections
Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections
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DOI：
10.1073/pnas.1719266115
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发表时间：
2018-07-03
影响因子：
11.1
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
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作者：
Muffat, Julien;Li, Yun;Jaenisch, Rudolf
妊娠期间的母体寨卡病毒（ZIKV）感染被认为是人类胎儿中流行性小头畸形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）的高度脆弱的神经祖细胞群体，以及CNS的哪些细胞类型可能是病毒储库。相反，相关的登革病毒（DENV）不会引起致畸性。为了在体外模拟病毒与胎儿CNS细胞的相互作用，我们研究了ZIKV和DENV对不同的诱导多能干细胞衍生的人细胞的向性，特别关注小胶质细胞样细胞。我们表明ZIKV感染同基因神经祖细胞、星形胶质细胞和小胶质细胞样细胞（pMGL），但仅对神经祖细胞具有细胞毒性。感染的神经胶质细胞增殖ZIKV并随时间维持ZIKV负荷，导致病毒扩散至易感细胞。DENV引发更强的免疫应答，并且可以更有效地被神经细胞和胶质细胞清除。当与神经球状体共培养时，pMGL侵入组织，并且当用ZIKV感染时，引发神经感染。由于小神经胶质细胞来源于起源于母体脉管系统附近的原始巨噬细胞，因此它们可以充当ZIKV的病毒储库并建立胎儿脑的感染。小胶质细胞对未成熟神经干细胞的感染可能发生在妊娠早期，在脑内血管生成之前。我们的数据也与ZIKV和DENV影响血脑屏障的完整性一致，从而允许在以后的生活中感染大脑。
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.