寨卡病毒丨“特洛伊木马”式的母婴传播机制

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寨卡病毒丨“特洛伊木马”式的母婴传播机制

原创 2017-11-28 翻译丨张菊 SIFIC感染官微

检索丨陈志锦

翻译丨张菊

审核丨周超群 陈志锦

加利福尼亚大学圣地亚哥分校医学院的研究人员与巴西的同事们联合发表，寨卡病毒是通过感染的细胞从母体传染给胎儿的，具有讽刺意味的是，这种病毒最终会发展成大脑对侵入性病原体的首要的防御方式。

这一发现发表在最新一期的《人类分子遗传学》杂志上。

加州大学圣地亚哥医学院儿科细胞与分子医学系的教授Alysson Muotri博士说：“这是一种特洛伊木马的策略，在胚胎发育期间，即产前发育的早期阶段，称为小胶质细胞的细胞在卵黄囊中形成，然后分散到发育中的儿童的中枢神经系统（CNS）中。在大脑中，这些小胶质细胞将成为常驻巨噬细胞，其职责是不断清除斑块、受损细胞和感染因子。我们的研究结果表明，寨卡病毒可以感染这些早期的小胶质细胞，潜藏于大脑中，然后将病毒传播给其他脑细胞，最终导致我们在一些新生儿身上看到的破坏性神经损伤。”

从2015年开始，在巴西观察到小头畸形或其他出生缺陷的新生儿急剧增加。 这种现象随后在去年被Muotri和其他人在实验模型中证实与寨卡病毒感染有关。

通常情况下，寨卡病毒是通过被感染的伊蚊叮咬传播给人类的。然而，孕妇也可以将病毒传播给胎儿，尽管科学家们尚未准确地描述这种传播方式。

Muotri说:“考虑到传播的时机，我们推测小胶质细胞可能是在病毒入侵中枢神经系统时，起到了特洛伊木马的运输作用。”

为了验证他们的假设，研究人员利用人类诱导的多能干细胞制造了两种相关的中枢神经系统细胞类型:小胶质细胞和神经祖细胞(NPCs)，，它们在胚胎发育过程中产生了数百万个神经元和神经胶质细胞。然后，他们建立了一个共同培养系统，模拟了两种细胞在体外暴露于寨卡病毒时的相互作用。

他们发现小胶质细胞行使了他们的职能，吞噬了感染寨卡病毒的神经祖细胞（NPCs）。但是，当携带病毒的小胶质细胞与非感染的神经祖细胞（NPCs）接触时，就会将病毒传染给后者。Muotri说:“这意味着在产前神经发育过程中，小胶质细胞可能确实是将病毒传播到中枢神经系统的罪魁祸首。”

然后，Muotri和他的同事们测试了FDA批准的名为Sofosbuvir的药物，商品名为Sovaldi，用于治疗丙型肝炎，可能会限制共同培养系统中神经祖细胞（NPCs）和小胶质细胞之间的病毒感染。实际上它做到了。“Sofosbuvir显著降低了神经祖细胞（NPCs）的死亡率和病毒载量。”

尽管这些发现是基于体外研究的，并且需要进一步的研究，但是Muotri表示研究结果仍然令人鼓舞，这意味着小胶质细胞可能是降低寨卡病毒传播到发育中的胎儿中枢神经系统的治疗靶点。

他说:“我们开发的共同培养系统对研究神经-免疫的相互作用是非常有用的，它还能作为一个药物筛选平台，用于在人类背景下发现针对寨卡病毒感染的新型治疗化合物。”

原文：

Discovery may provide insight into howZukav virus gets transmitted from mother to fetus

Researchers at the University of CaliforniaSan Diego School of Medicine, with colleagues in Brazil, report that the Zikavirus is transmitted from mother to fetus by infected cells that, ironically,will later develop into the brain's first and primary form of defense againstinvasive pathogens.

The findings are published in the currentonline issue of Human Molecular Genetics.

"It's a Trojan Horse strategy,"said Alysson Muotri, PhD, professor in the UC San Diego School of Medicinedepartments of Pediatrics and Cellular and Molecular Medicine. "Duringembryogenesis -- the early stages of prenatal development -- cells calledmicroglia form in the yolk sac and then disperse throughout the central nervoussystem (CNS) of the developing child.

"In the brain, these microglia willbecome resident macrophages whose job is to constantly clear away plaques,damaged cells and infectious agents. Our findings show that the Zika virus caninfect these early microglia, sneaking into the brain where they transmit thevirus to other brain cells, resulting in the devastating neurological damage wesee in some newborns."

Beginning in 2015, a dramatic increase inchildren born with microcephaly or abnormally small heads and other birthdefects was observed in Brazil. The phenomenon was subsequently linked toinfection by the Zika virus, which Muotri and others confirmed last year causedbirth defects in experimental models.

Typically, the Zika virus is transmitted topeople through the bite of infected Aedes species mosquitoes. However, apregnant woman can also pass the virus to her fetus, though scientists have notbeen able to precisely describe the mode of transmission.

"Considering the timing oftransmission, we hypothesized that microglia might be serving as a Trojan horseto transport the virus during invasion of the CNS," Muotri said.

To test their hypothesis, the researchersused human induced pluripotent stem cells to create two relevant CNS celltypes: microglia and neural progenitor cells (NPCs), which generate themillions of neurons and glial cells required during embryonic development. Thenthey established a co-culture system that mimicked the interactions of the twocell types in vitro when exposed to the Zika virus.

They found that the microglia cellsengulfed Zika-infected NPCs, doing their job. But when these microglia carryingthe virus were placed in contact with non-infected NPCs, they transmitted thevirus to the latter. "That suggests microglia may indeed be the culpritfor transmitting the virus to the CNS during prenatal neurodevelopment,"Muotri said.

Muotri and colleagues then tested whetheran FDA-approved drug called Sofosbuvir, marketed as Sovaldi and used to treathepatitis C, might limit viral infection of NPCs in co-culture with infectedmicroglia. It did. "Sofosbuvir significantly decreased cell death of NPCsand the viral load in NPCs"

Though the findings are based on in vitroresearch and further investigation is necessary, Muotri said they were encouraging,suggesting microglial cells could be a therapeutic target for reducing Zikatransmission into the CNS of developing fetuses.

"The co-culture system we've developedis robust and useful for studying neuro-immune interactions," he said."It can also serve as a drug-screening platform for discovering newtherapeutic compounds against Zika virus infections in a human context."

Source:http://ucsdnews.ucsd.edu/pressrelease/zika_virus_infects_developing_brain_by_first_infecting_cells_meant_to_defen

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