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Molecular insights into the effects of SARS-Cov2 infection on the blood system

SARS-Cov2 感染对血液系统影响的分子洞察

基本信息

批准号：
10929202
负责人：
Naoko Mizuno
金额：
$ 53.69万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929202
关键词：
2019-nCoV ACE2 Adopted Affinity Antiphospholipid Antibodies Behavior Binding Blood Blood Coagulation Disorders Blood Platelets COVID-19 COVID-19 pathogenesis COVID-19 patient Cardiovascular system Cell-Matrix Junction Cells China Coagulation Process Collagen Coronavirus Cryo-electron tomography Development Disease Disease Outbreaks Disseminated Intravascular Coagulation Docking Endocytosis Epidemic Extracellular Matrix Family Fatal Outcome Filopodia Heart Image Immune Immune response Infection Integrins Intestines Kidney Lateral Long-Term Effects Lung Membrane Middle East Respiratory Syndrome Coronavirus Minor Molecular Molecular Conformation Morphology Multiple Organ Failure Myocardial Infarction Nucleocapsid Pathogenicity Patients Peptide Hydrolases Platelet Activation Platelet Count measurement Proteins RNA Viruses Reporting Resolution Respiratory Failure Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 spike protein Severe Acute Respiratory Syndrome Shock Site Surface Symptoms Syndrome System TLR4 gene Testing Thrombocytopenia Tissues Viral Virus Virus Activation Visualization betacoronavirus cytokine flexibility immunothrombosis inhibitor insight member neutrophil novel particle pathogen pathogenic virus receptor receptor binding respiratory thrombotic complications

项目摘要

We hypothesize that SARS-Cov2 directly interacts with neutrophils as well as platelets through their receptors, and induces a change in platelet morphology, leading to their activation and coagulation. We performed live imaging showing that platelets are directly activated in the presence of purified SARS-Cov2 spike protein. Particularly, prominent effects were shown under collagen-I ECM background. We further visualized platelet deformation in the presence of SARS-Cov2 spike protein using cellular cryo-electron tomography (cryo-ET). Strikingly, cellular cryo-ET revealed dense decorations of SARS-CoV-2 spike protein on the platelet surface coinciding with filopodia formation. Further analysis including sub-tomogram averaging up to 12 resolution revealed the flexible attachment of the SARS-CoV-2 to the membrane surface, suggesting a great adoptability of the SARS-CoV-2 spike protein to the dynamic membrane surface. We further tested the binding to several platelet receptors and the receptor inhibitors. We demonstrated the SARS-CoV-2 spike protein has a weak affinity to a5b1 as well as avb3, but not aIIbb3 integrin receptors. Our results infer that the stochastic activation of platelets is due to weak the interactions of SARS-CoV-2 spike protein with minor integrins expressed on platelet surface, which can attribute to the multilateral pathogenesis of COVID-19 and the occurrence of rare but severe coagulopathies.

我们假设SARS-Cov 2通过其受体直接与中性粒细胞和血小板相互作用，并诱导血小板形态的变化，导致其活化和凝血。我们进行了实时成像，显示血小板在纯化的SARS-Cov 2刺突蛋白存在下直接活化。特别地，在胶原-I ECM背景下显示出显著的效果。我们使用细胞冷冻电子断层扫描（cryo-ET）进一步观察了SARS-Cov 2刺突蛋白存在下的血小板变形。引人注目的是，细胞冷冻ET显示血小板表面SARS-CoV-2刺突蛋白的密集装饰与丝状伪足形成一致。进一步的分析，包括亚断层图像平均高达12分辨率显示的灵活的附件的SARS-CoV-2的膜表面，表明一个很大的适应性的SARS-CoV-2刺突蛋白的动态膜表面。我们进一步测试了与几种血小板受体和受体抑制剂的结合。我们证明SARS-CoV-2刺突蛋白对a5 b1和avb 3具有弱亲和力，但对aIIbb 3整合素受体没有亲和力。我们的研究结果推断，血小板的随机激活是由于SARS-CoV-2刺突蛋白与血小板表面表达的次要整合素的相互作用较弱，这可能归因于COVID-19的多边发病机制和罕见但严重的凝血功能障碍的发生。