Institute of NeuroImmune Pharmacology, South Orange, NJ 07079, USA.
Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA.
Int J Mol Sci. 2023 Aug 31;24(17):13554. doi: 10.3390/ijms241713554.
Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a "cytokine storm", and neuroinflammation. COVID-19's upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the () gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN's Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of , and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on activation.
新型冠状病毒病（COVID-19）是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）感染引起的。病毒通过血管紧张素转换酶 2（ACE2）受体介导的内吞作用进入宿主细胞，导致全身炎症，也称为“细胞因子风暴”和神经炎症。COVID-19 的上游调节剂干扰素-γ（IFNG）在感染 SARS-CoV-2 后下调，导致 ACE2 下调。神经炎症信号通路（NISP）可导致神经退行性疾病，如帕金森病（PD），其特征是主要由 ()基因编码的α-突触核蛋白形成路易体。我们假设 COVID-19 可能通过细胞因子风暴引起的神经炎症来调节 PD 的进展。本研究旨在阐明 COVID-19 引发与 PD 等神经退行性疾病相关的病理学的可能机制和信号通路。本研究分析了 SARS-CoV-2 感染后 ACE2 下调及其对 PD 进展影响的相关通路。通过 QIAGEN 的 Ingenuity 通路分析（IPA），该研究确定了 NISP 作为前五名的经典通路/信号通路和作为前五名的上游调节剂。还对 COVID-19 和 之间的相关分子进行了核心分析，以构建网络连接图。使用分子活性预测器工具模拟 SARS-CoV-2 的感染，通过中间分子数据集下调 IFNG，导致预测的 激活，随后通过数据集预测 PD。进一步使用下游效应分析来量化 ACE2 下调对 激活的影响。
