Mechanisms of atherosclerotic cardiovascular complications in COVID19

项目摘要 2019冠状病毒病（COVID-19）大流行，由严重急性呼吸系统综合征冠状病毒引起 2（SARS-CoV-2）仍然是一个全球健康问题，尽管疫苗的快速发展和 新的抗病毒药物的前景迫在眉睫，预计将成为流行病。COVID-19与 动脉粥样硬化性心血管（CV）并发症，如急性冠状动脉综合征（ACS）、心肌梗死 (MI)和中风，这种风险在恢复后的一年内仍然很高，但其潜在机制 我们对此知之甚少。在初步工作中，使用了来自COVID-19患者尸检的动脉粥样硬化组织， 从COVID-19中康复的受试者，沿着人血管外植体的离体SARS-CoV-2模型， 我们在人类斑块中发现了SARS-CoV-2病毒物质，这些物质在康复患者的斑块中持续存在， 从COVID-19人类动脉粥样硬化斑块的单细胞RNA测序（scRNAseq）鉴定出高水平 神经纤毛蛋白-1（NRP 1），一种SARS冠状病毒进入的受体，在斑块巨噬细胞和泡沫细胞中。NRP-1 阻断消除了病毒物质在SARS-CoV-2处理的人噬斑中的积累。这些数据 表明SARS-COV-2或其病毒成分可以在人体斑块中积累， 炎症和疾病的进展。使用叙利亚金黄仓鼠模型， 忠实地模仿人类SARS-CoV 2感染，我们发现，病毒复制在心脏，肺和嗅觉， 感染仓鼠的睾丸与Ace 2的表达水平无关，这支持了Ace 2替代表达的作用。 病毒进入的机制，如NRP-1。此外，该模型揭示了急性和持续的组织特异性 在几种组织中的炎性反应（即Nfkb 1，IL 6，IL 1b），由于持续存在于循环中， 非感染性病毒RNA碎片（vRNA）在病毒清除后长达数周。基于这些令人兴奋的 初步数据，我们提出了两个独立的目标，研究如何SARS-CoV-2加剧斑块炎症 和动脉粥样硬化，并确定急性和长期CV事件风险增加的分子基础 在COVID-19患者中。在目的1中，我们将确定NRP-1在SARS-CoV-2诱导的动脉粥样硬化斑块中的作用。 炎症和动脉粥样硬化进展。目的2将确定SARS-CoV-2 vRNA碎片的贡献 炎症和动脉粥样硬化。我们还将确定持续性vRNA对炎症的影响， 在病毒清除和从COVID-19恢复后的动脉粥样硬化形成。这些研究将解决重要的差距 了解SARS-CoV-2感染对斑块炎症和动脉粥样硬化的影响，并将解决 COVID-19患者CV增加的分子基础。我们预见这些信息将有助于 指导未来精确治疗的设计，以预防COVID-19患者的CV结局。

PROJECT SUMMARY The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global health concern and despite the fast-track development of vaccines and the imminent prospective of new antiviral drugs, is expected to become endemic. COVID-19 is associated with atherosclerotic cardiovascular (CV) complications like acute coronary syndrome (ACS), Myocardial Infarction (MI) and stroke, a risk that remains high for up to one year following recovery, but the underlying mechanisms are poorly understood. In preliminary work using atherosclerotic tissue from COVID-19 patients at autopsy and subjects who recovered from COVID-19, along with an ex-vivo SARS-CoV-2 model of human vascular explants, we identified SARS-CoV-2 viral material in human plaques that persists in plaques of patients who recovered from COVID-19. Single cell RNA sequencing (scRNAseq) of human atherosclerotic plaques identified high levels of neuropilin-1 (NRP1), a receptor for SARS-CoV-2 entry, in plaque macrophages and foam cells. NRP-1 blockade abrogated the accumulation of viral material in SARS-CoV-2 treated human plaques. These data suggest that SARS-COV-2 or its viral components can accumulate in human plaques, where they exacerbate inflammation and disease progression by engaging NRP-1. Using the Syrian Golden hamster model, that faithfully mimics human SARS-CoV2 infection, we found that viral replication in the heart, lungs and olfactory bulb of infected hamsters did not correlate with expression levels of Ace2, supporting a role for alternative mechanisms of viral entry such as NRP-1. Moreover, this model revealed acute and sustained tissue-specific inflammatory responses (i.e. Nfkb1, Il6, Il1b) in several tissues due to the persistence in the circulation of noninfectious viral RNA debris (vRNA) for up to several weeks following viral clearance. Based on these exciting preliminary data, we propose two independent aims to study how SARS-CoV-2 aggravates plaque inflammation and atherosclerosis and to determine the molecular basis for the increased risk of acute and long-term CV events in COVID-19 patients. In Aim 1 we will identify the role of NRP-1 in SARS-CoV-2-induced atherosclerotic plaque inflammation and atherosclerosis progression. Aim 2 will identify the contribution of SARS-CoV-2 vRNA debris to inflammation and atherosclerosis. We will also determine the effect of persistent vRNA on inflammation and atherogenesis following viral clearance and recovery from COVID-19. These studies will address important gaps in knowledge on the effect of SARS-CoV-2 infection on plaque inflammation and atherosclerosis, and will tackle the molecular basis for the increased CV in patients with COVID-19. We foresee that this information will help guide the future design of precise therapies to prevent CV outcomes in patients with COVID-19.