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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 2019 年冠状病毒病 (COVID-19) 大流行，由严重急性呼吸系统综合症冠状病毒引起 2（SARS-CoV-2）仍然是一个全球健康问题，尽管疫苗和疫苗的快速开发新型抗病毒药物前景迫在眉睫，有望成为流行病。 COVID-19 与动脉粥样硬化性心血管 (CV) 并发症，如急性冠脉综合征 (ACS)、心肌梗塞 (MI) 和中风，这种风险在康复后长达一年内仍然很高，但其潜在机制人们了解甚少。在初步工作中，使用尸检时来自 COVID-19 患者的动脉粥样硬化组织从 COVID-19 中康复的受试者，以及人类血管外植体的离体 SARS-CoV-2 模型，我们在人类斑块中发现了 SARS-CoV-2 病毒物质，该物质在康复患者的斑块中持续存在来自新冠肺炎 (COVID-19)。人类动脉粥样硬化斑块的单细胞 RNA 测序 (scRNAseq) 发现高水平斑块巨噬细胞和泡沫细胞中的神经毡蛋白-1 (NRP1)（SARS-CoV-2 进入的受体）。 NRP-1 封锁消除了经 SARS-CoV-2 处理的人类斑块中病毒物质的积累。这些数据表明 SARS-COV-2 或其病毒成分可以在人体斑块中积聚，从而加剧通过参与 NRP-1 来促进炎症和疾病进展。使用叙利亚金仓鼠模型，忠实地模仿人类 SARS-CoV2 感染，我们发现病毒在心脏、肺和嗅觉中复制受感染仓鼠的球茎与 Ace2 的表达水平不相关，支持替代方案的作用病毒进入的机制，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中的持续存在，多种组织中的炎症反应（即 Nfkb1、Il6、Il1b）病毒清除后长达数周的非感染性病毒 RNA 碎片 (vRNA)。基于这些激动人心的根据初步数据，我们提出两个独立的目标来研究 SARS-CoV-2 如何加重斑块炎症和动脉粥样硬化，并确定急性和长期心血管事件风险增加的分子基础在 COVID-19 患者中。在目标 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。目标 2 将确定 SARS-CoV-2 vRNA 碎片的贡献炎症和动脉粥样硬化。我们还将确定持久性 vRNA 对炎症和病毒清除和 COVID-19 恢复后的动脉粥样硬化。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。我们预计这些信息将有所帮助指导未来精确疗法的设计，以预防 COVID-19 患者的心血管结局。