Neurons are the Primary Target Cell for the Brain-Tropic Intracellular Parasite Toxoplasma gondii.
Neurons are the Primary Target Cell for the Brain-Tropic Intracellular Parasite Toxoplasma gondii.
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DOI：
10.1371/journal.ppat.1005447
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发表时间：
2016-02
期刊：
影响因子：
6.7
通讯作者：
Koshy AA
中科院分区：
文献类型：
--
作者：
Cabral CM;Tuladhar S;Dietrich HK;Nguyen E;MacDonald WR;Trivedi T;Devineni A;Koshy AA
弓形虫是一种常见的嗜脑寄生虫，在体外能够感染大多数有核细胞，包括星形胶质细胞和神经元。然而，在体内，弓形虫主要存在于神经元中。体外数据显示，干扰素-γ刺激的星形胶质细胞，而不是神经元，清除了细胞内的寄生虫，这表明神经元本身在体内持续感染，因为它们缺乏清除细胞内寄生虫的能力。在这里，我们使用一种新的弓形虫-小鼠模型来测试这一理论，该模型能够标记和跟踪与寄生虫直接相互作用的宿主细胞，即使这种相互作用是暂时的。值得注意的是，我们发现弓形虫在整个中枢神经系统感染过程中表现出强烈的与神经元相互作用的偏好。这种偏好仍然存在于干扰素-γ耗尽、感染对小鼠星形胶质细胞清除寄生虫的主要机制产生抗药性的寄生虫、或直接将寄生虫注入大脑的情况下。这些发现，结合之前的工作，强烈表明神经元不是偶然感染的，而是弓形虫在体内的主要目标。弓形虫是一种普遍存在的细胞内寄生虫，慢性感染多达三分之一的世界人口的大脑。虽然大多数感染者没有症状，但弓形虫对大脑的趋向性是这种寄生虫在发育中的胎儿和免疫系统受损的人(如艾滋病或器官移植患者)导致衰弱神经疾病的能力的基础。我们对大脑中哪些细胞与弓形虫相互作用以及被弓形虫感染的了解主要来自于组织培养方面的工作，组织培养不能重新屈服于活动物的复杂性。在这里，我们通过使用一种新的小鼠模型来研究脑与弓形虫的相互作用来克服这一障碍，该模型允许我们永久标记和跟踪与寄生虫相互作用的脑细胞。与细胞培养相反，我们发现在急性和慢性脑感染过程中，弓形虫几乎只与神经元相互作用，很少与星形胶质细胞相互作用。这种神经元偏好即使在被高度操控的情况下也会持续存在，比如将寄生虫直接引入大脑。这项工作首次表明弓形虫在体内主要与神经元相互作用，这表明要了解弓形虫持续感染大脑的能力，必须了解神经元与弓形虫的相互作用。
Toxoplasma gondii, a common brain-tropic parasite, is capable of infecting most nucleated cells, including astrocytes and neurons, in vitro. Yet, in vivo, Toxoplasma is primarily found in neurons. In vitro data showing that interferon-γ-stimulated astrocytes, but not neurons, clear intracellular parasites suggest that neurons alone are persistently infected in vivo because they lack the ability to clear intracellular parasites. Here we test this theory by using a novel Toxoplasma-mouse model capable of marking and tracking host cells that directly interact with parasites, even if the interaction is transient. Remarkably, we find that Toxoplasma shows a strong predilection for interacting with neurons throughout CNS infection. This predilection remains in the setting of IFN-γ depletion; infection with parasites resistant to the major mechanism by which murine astrocytes clear parasites; or when directly injecting parasites into the brain. These findings, in combination with prior work, strongly suggest that neurons are not incidentally infected, but rather they are Toxoplasma’s primary in vivo target. Toxoplasma gondii is a ubiquitous intracellular parasite that chronically infects the brain of up to 1/3 of the world’s population. While most infected persons have no symptoms, Toxoplasma’s tropism for the brain underlies the parasite’s ability to cause debilitating neurologic disease in the developing fetus and the immunocompromised, such as AIDS or organ transplant patients. Our understanding of which cells of the brain interact with and are infected by Toxoplasma primarily comes from work in tissue culture, which cannot re-capitulate the complexity of a living animal. Here, we overcome this barrier by studying brain-Toxoplasma interactions using a novel mouse model that allows us to permanently mark and track brain cells that have interacted with parasites. Contrary to what has been shown in cell culture, we find that throughout acute and chronic brain infection Toxoplasma almost exclusively interacts with neurons, and rarely interacts with astrocytes. This neuronal predilection persists even in highly manipulated circumstances such as the introduction of parasites directly into the brain. This work is the first to show that Toxoplasma primarily interacts with neurons in vivo, which suggests that to understand Toxoplasma’s ability to persistently infect the brain, we must understand the neuron-Toxoplasma interaction.