Mechanisms of atherosclerotic cardiovascular complications in COVID19

新冠肺炎动脉粥样硬化性心血管并发症的机制

• 批准号: 10512449
• 负责人: Chiara Giannarelli
• 金额: $ 80.37万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512449
• 关键词: 2019-nCoV; ACE2; Acute; Address; Adverse effects; Affect; Antiviral Agents; Arterial Fatty Streak; Atherosclerosis; Autopsy; Biological Assay; Blood; Blood Circulation; Blood Vessels; Bone Marrow; COVID-19; COVID-19 impact; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cardiovascular system; Cells; Clinical Sciences; Data; Detection; Disease Progression; Event; Exposure to; Foam Cells; Future; Genes; Goals; Hamsters; Heart; Hematopoietic; Histologic; Human; Immune; Immune response; Immunofluorescence Immunologic; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Knowledge; Lung; Measures; Mediating; Medical center; Mesocricetus auratus; Modeling; Molecular; Monitor; Myocardial Infarction; NRP1 gene; Neuropilin-1; New York City; Nucleocapsid Proteins; Organ; Outcome; PTPRC gene; Patients; Post-Acute Sequelae of SARS-CoV-2 Infection; Public Health; Recovery; Resolution; Risk; Role; SARS-CoV-2 infection; Spleen; Stroke; Testing; Tissues; United States National Institutes of Health; Viral; Virus; Virus Replication; Work; X-Ray Computed Tomography; acute coronary syndrome; acute infection; atherogenesis; base; biobank; cardiovascular risk factor; clinically relevant; coronavirus disease; cytokine; design; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; global health; human RNA sequencing; human data; human model; indexing; individualized medicine; lipid metabolism; macrophage; molecular targeted therapies; molnupiravir; olfactory bulb; prevent; prospective; receptor; response; single cell analysis; single-cell RNA sequencing; small molecule inhibitor; systemic inflammatory response; transcriptome; vaccine development; viral RNA; western diet

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.

项目摘要 严重急性呼吸综合征冠状病毒引起的2019年冠状病毒病（COVID-19）大流行 2（SARS-COV-2）仍然是全球健康问题，尽管疫苗和疫苗快速发展 迫在眉睫的新抗病毒药物预计将成为地方性。 COVID-19与 动脉粥样硬化心血管（CV）并发症，如急性冠状动脉综合征（ACS），心肌梗塞 （MI）和中风，这种风险在恢复后长达一年，但基本机制仍然很高 知之甚少。在初步工作中，使用尸检中的COVID-19患者的动脉粥样硬化组织和 从Covid-19恢复的受试者，以及人类血管外植体的前体体SARS-COV-2模型 我们在人斑块中确定了SARS-COV-2病毒材料，这些病毒材料持续存在于恢复的患者斑块中 从Covid-19。人动脉粥样硬化斑块的单细胞RNA测序（SCRNASEQ）鉴定出高水平 在斑块巨噬细胞和泡沫细胞中，Neuropilin-1（NRP1）是SARS-COV-2进入的受体。 NRP-1 封锁废除了SARS-COV-2处理过的人斑的病毒物质的积累。这些数据 表明SARS-COV-2或其病毒成分可以在人斑中积聚，在那里它们加剧 通过参与NRP-1的炎症和疾病进展。使用叙利亚金仓鼠模型， 忠实地模仿了人类sars-cov2感染，我们发现心脏，肺和嗅觉中的病毒复制 囊泡受感染的仓鼠与ACE2的表达水平无关，支持替代角色 病毒进入的机制，例如NRP-1。此外，该模型揭示了急性和持续的组织特异性 由于循环的持续存在，在几种组织中的炎症反应（即NFKB1，IL6，IL1B） 病毒清除后，非感染病毒RNA碎片（VRNA）长达几周。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，以研究SARS-COV-2如何加剧斑块炎症 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199位患者中。在AIM 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。 AIM 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对炎症和 病毒清除率和从Covid-19的恢复后的动脉粥样硬化。这些研究将解决重要的差距 关于SARS-COV-2感染对斑块炎症和动脉粥样硬化的影响的知识，并将解决 COVID-19患者CV增加的分子基础。我们预见到这些信息将有所帮助 指导精确疗法的未来设计，以防止COVID-19患者的简历结局。