National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27518, USA.
Johns Hopkins University, Baltimore, MD 21205, USA.
Cells. 2022 Oct 28;11(21):3411. doi: 10.3390/cells11213411.
Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood-brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.
已有多项报告表明，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）也具有神经嗜性。然而，SARS-CoV-2 引发神经损伤（包括神经系统和/或心理症状）的机制仍不清楚。在本综述中，使用 AOP 框架对与 COVID-19 相关的神经生物学机制的现有知识进行了组织。制定了四个导致神经不良结局（AO）、嗅觉丧失、脑炎、中风和癫痫的 AOP。确定可诱发这些 AOs 的生物学关键事件（KEs）包括与 ACE2 的结合、血脑屏障（BBB）破坏、缺氧、神经炎症和氧化应激。AOP 的模块化允许构建 AOP 网络，以可视化核心途径，并将神经炎症和 BBB 破坏视为共享机制。此外，还讨论了调节和多尺度因素（如年龄、心理压力、营养、贫困和粮食不安全）对 COVID-19 神经 AOP 的影响。沿着 AOP 框架组织现有知识可以代表一种理解疾病机制和识别数据空白的有价值工具，并可能有助于治疗和预防。这种与 AOP 一致的方法还促进了来自不同背景的专家之间的协同作用，而 COVID-19 的快速发展和颠覆性性质强调了跨学科和跨社区研究的必要性。
