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.

中文翻译：

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COVID-19 患者脑部感染的形态学、细胞和分子基础

尽管越来越多的证据证实主要与严重 COVID-19 感染相关的神经精神表现，但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系统综合症冠状病毒 2 (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）到严重急性感染从死于 COVID-19 的个体的眶额区域（通过鼻内经筛道通路）提取的脑组织样本中证实了损伤。在一个由 26 名死于 COVID-19 的人组成的独立队列中，我们使用脑损伤的组织病理学迹象作为可能的 SARS-CoV-2 脑部感染的指南，并发现在表现出这些迹象的 5 个人中，他们的大脑中都有该病毒的遗传物质。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假说的是，神经干细胞衍生的人星形胶质细胞在体外容易通过一种非典型机制感染 SARS-CoV-2，该机制涉及刺突-NRP1 相互作用。感染 SARS-CoV-2 的星形胶质细胞表现出能量代谢和用于为神经元提供能量的关键蛋白质和代谢物以及神经递质的生物发生方面的变化。此外，人类星形胶质细胞感染会引发分泌表型，从而降低神经元活力。我们的数据支持 SARS-CoV-2 到达大脑、感染星形胶质细胞并因此导致神经元死亡或功能障碍的模型。这些解除管制的过程可能导致 COVID-19 患者大脑中的结构和功能改变。