Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.
Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.
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DOI：
10.1073/pnas.2200960119
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发表时间：
2022-08-30
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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神经系统症状是COVID-19最常见的肺外并发症之一，影响超过30%的患者。在这项研究中，我们提供的证据表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是在人类大脑中发现的，它感染星形胶质细胞，并在较小程度上，神经元。我们还表明，星形胶质细胞容易受到SARS-CoV-2感染，通过一个非经典的机制，涉及尖峰-NRP 1的相互作用，并通过重塑能量代谢，这反过来又改变了用于燃料神经元和支持神经递质合成的代谢产物的水平的感染。受感染的星形胶质细胞的分泌表型改变，然后损害神经元的活力。这些特征可以解释在COVID-19患者大脑中观察到的损伤和结构变化。尽管越来越多的证据证实神经精神表现主要与严重COVID-19感染相关，但在轻度感染后经常观察到长期神经精神功能障碍（最近被定性为“长期COVID-19”综合征的一部分）。我们展示了严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染对大脑的影响范围，从轻度感染个体的长期改变（眶额皮质萎缩、神经认知障碍、过度疲劳和焦虑症状）到严重急性损伤，这些损伤在从死于COVID-19的个体的眶额区（通过鼻内经筛窦入路）提取的脑组织样本中得到证实。在一个由26名死于COVID-19的个体组成的独立队列中，我们使用脑损伤的组织病理学体征作为可能的SARS-CoV-2脑感染的指导，发现在表现出这些体征的5名个体中，所有人的大脑中都有病毒的遗传物质。这五名患者的脑组织样本也显示出SARS-CoV-2感染和复制的病灶，特别是在星形胶质细胞中。支持星形胶质细胞感染的假设，神经干细胞衍生的人星形胶质细胞在体外通过非经典机制，涉及尖峰-NRP 1相互作用对SARS-CoV-2感染易感。SARS-CoV-2感染的星形胶质细胞表现出能量代谢、用于为神经元提供燃料的关键蛋白质和代谢物以及神经递质生物发生的变化。此外，人星形胶质细胞感染elevites分泌表型，降低神经元的活力。我们的数据支持SARS-CoV-2到达大脑，感染星形胶质细胞，从而导致神经元死亡或功能障碍的模型。这些失调的过程可能有助于在COVID-19患者的大脑中观察到的结构和功能改变。
Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30% of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in the human brain, where it infects astrocytes and to a lesser extent, neurons. We also show that astrocytes are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction and respond to the infection by remodeling energy metabolism, which in turn, alters the levels of metabolites used to fuel neurons and support neurotransmitter synthesis. The altered secretory phenotype of infected astrocytes then impairs neuronal viability. These features could explain the damage and structural changes observed in the brains of COVID-19 patients. Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
影响因子：
30.3
作者：
Case, James Brett;Rothlauf, Paul W.;Whelan, Sean P. J.
通讯作者：
Whelan, Sean P. J.
影响因子：
3.4
作者：
Bonansco, Christian;Couve, Alejandro;Fuenzalida, Marco
通讯作者：
Fuenzalida, Marco
影响因子：
4.2
作者：
Bettcher BM;Olson KE;Carlson NE;McConnell BV;Boyd T;Adame V;Solano DA;Anton P;Markham N;Thaker AA;Jensen AM;Dallmann EN;Potter H;Coughlan C
通讯作者：
Coughlan C
影响因子：
64.8
作者：
通讯作者：
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