MiRNA-based Therapeutics for SARS-CoV-2 S1 mediated neuroinflammation and beta-amyloid production

项目摘要/摘要 有充分证据表明，新冠肺炎的病原体SARS-CoV-2会导致 神经症状，但没有足够的证据表明病毒可以直接感染大脑。 有人提出，神经系统症状可能是由于其他因素造成的，例如 细胞因子风暴、神经免疫刺激和系统性SARS-CoV-2感染，而不是通过 病毒对中枢神经系统的直接损害。S蛋白是SARS的主要抗原组分-- CoV-2结构蛋白及其蛋白降解处理允许S1亚基解离，该亚基 然后触发融合所需的S2亚基重排。此外，TLR4是最多的 TLR家族的重要成员，用于病原体识别，并帮助提供第一线 通过炎症因子诱导防御感染。在此，我们建议测试 假设被切割的S1亚基本身进入脑实质，导致 神经炎症和b-淀粉样蛋白积聚和TLR4靶向的microRNA(S)可以抑制这些作用 流程。这一假设将在两个具体目标上得到检验。第一, 我们将直接测试S1是否 与小胶质细胞中的TLR4相互作用，启动免疫反应，导致过度激活 破坏免疫平衡，导致慢性脑部炎症 和b-淀粉样蛋白堆积。其次，我们将测试使用以下方法选择的特定miRNA的作用 生物信息学预测工具，在调节S1启动的神经炎症中。之后 MiRNA靶标的实验验证，特定的miRNAs将富含在外切体和 测试他们终止炎症和b-淀粉样蛋白之间的正反馈循环的能力 制作。预计这一结果将为理解新冠肺炎效应提供机械性的见解 关于神经炎症和痴呆的研究，并导致miRNA治疗药物的发展 Covid诱导的炎症和b-淀粉样蛋白产生之间的调节环路。

Project summary/Abstract There is ample evidence that SARS-CoV-2, the causative agent of COVID-19, causes neurological symptoms but there is insufficient evidence that the virus can directly infect the brain. It has been suggested that neurological symptoms might be due to additional factors such as cytokine storm, neuroimmune stimulation, and systemic SARS-CoV-2 infection, rather than by direct CNS damage caused by the virus. The S protein is the main antigenic component of SARS- CoV-2 structural protein and its proteolytic processing allows the S1 subunit to dissociate, which then triggers the S2 subunit rearrangement that is required for fusion. Also, TLR4 is the most important member of the TLR family for pathogen recognition and helps to provide first line defense against infections through inflammatory factors induction. Herein, we propose to test the hypothesis that the cleaved S1 subunit itself enters the brain parenchyma causing neuroinflammation and b-amyloid accumulation and TLR4-targeted microRNA(s) can inhibit these processes. This hypothesis will be tested in two specific aims. First, we will test if S1 directly interacts with TLR4 in microglia and initiates immune responses that leads to excessive activation of the pathway, which disrupts immune homeostasis and results in chronic brain inflammation and b-amyloid accumulation. Second, we will test the role of specific miRNAs, selected using bioinformatics prediction tools, in regulating the S1-initiated neuroinflammation. After experimental validation of miRNA targets, specific miRNAs will be enriched in exosomes and tested for their ability to end the positive feedback loop between inflammation and b-amyloid production. The results are expected to provide mechanistic insights into the COVID-19 effects on neuroinflammation and dementia and lead to the development of miRNA therapeutics against covid-induced regulatory loop between inflammation and b-amyloid production.