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RAPID: What is the role of extracellular vimentin in SARS2 host cell entry?

RAPID：细胞外波形蛋白在 SARS2 宿主细胞进入中起什么作用？

基本信息

批准号：
2032861
负责人：
Alison Patteson
金额：
$ 19.65万
依托单位：
Syracuse University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032861&HistoricalAwards=false
关键词：
RAPID What role extracellular vimentin

项目摘要

This project will determine the mechanisms by which cell surface vimentin modulates the cellular uptake of the novel virus SARS-CoV-2 (SARS2). Vimentin is an intermediate filament that forms part of the cellular cytoskeleton. New evidence indicates that vimentin is present on the extracellular surface of cells and plays a critical role in the binding and uptake of multiple viruses; yet, the mechanisms by which this happens remain unclear. Identifying the factors that regulate cell surface vimentin and how it interacts with SARS2 will provide new insight into new functions of cell surface vimentin and the fundamental mechanisms by which viruses infect cells. There is an urgent need for this information as we have an incomplete understanding of how this virus enters the cell. This project integrates techniques from physics, engineering, chemistry, and biology and will broaden participation in the field of biophysics by providing interdisciplinary training for graduate students and postdocs.Host cell entry of SARS2 is not yet fully characterized, but inhibition of both endocytosis and direct fusion are known to be preventative. SARS2 makes use of a spike protein to interact with the angiotensin converting enzyme 2 (ACE2) cellular receptor to drive host cell entry via membrane fusion. The membrane fusion pathway for SARS2 is, therefore, similar to SARS-CoV (SARS), the virus that genetically most closely resembles SARS2. Endocytosis is another dominant pathway for host cell entry, but the mechanisms involved remains largely unknown. Previous studies indicate that SARS host cell entry via endocytosis critically involves cell surface vimentin. This project aims to determine the role of cell surface vimentin in SARS2 cellular uptake. This project pursues the following three objectives: 1) determine the presence and the factors that regulate extracellular vimentin using fibroblasts and lung epithelial cells; 2) study the effect of extracellular vimentin on SARS2 viral uptake and determine whether viral uptake can be blocked by anti-vimentin antibodies; and 3) quantify the molecular interaction between vimentin and the spike protein of SARS2. These studies will be conducted using SARS2 virus-like particles. Results from molecular dynamics simulations will provide an interpretative framework for the experimental results.This RAPID award is made by the Cellular Dynamics and Functionl Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将确定细胞表面波形蛋白调节新型病毒SARS-CoV-2（SARS 2）细胞摄取的机制。波形蛋白是形成细胞骨架的一部分的中间丝。新的证据表明，波形蛋白存在于细胞的细胞外表面，并在多种病毒的结合和摄取中起着关键作用;然而，这种情况发生的机制仍不清楚。确定调节细胞表面波形蛋白的因子以及它如何与SARS 2相互作用，将为细胞表面波形蛋白的新功能和病毒感染细胞的基本机制提供新的见解。我们迫切需要这些信息，因为我们对这种病毒如何进入细胞还不完全了解。该项目整合了物理学、工程学、化学和生物学的技术，并将通过为研究生和博士后提供跨学科培训来扩大生物物理学领域的参与。SARS 2的宿主细胞进入尚未完全表征，但已知抑制内吞作用和直接融合是预防性的。SARS 2利用刺突蛋白与血管紧张素转换酶2（ACE 2）细胞受体相互作用，以通过膜融合驱动宿主细胞进入。因此，SARS 2的膜融合途径与SARS-CoV（SARS）相似，SARS-CoV（SARS）是基因上最相似的病毒。内吞作用是进入宿主细胞的另一个主要途径，但其机制仍不清楚。以往的研究表明，SARS宿主细胞通过内吞作用进入关键涉及细胞表面波形蛋白。本项目旨在确定细胞表面波形蛋白在SARS 2细胞摄取中的作用。本项目追求以下三个目标：1）使用成纤维细胞和肺上皮细胞确定细胞外波形蛋白的存在和调节因素; 2）研究细胞外波形蛋白对SARS 2病毒摄取的影响，并确定是否可以通过抗波形蛋白抗体阻断病毒摄取; 3）量化波形蛋白和SARS 2的刺突蛋白之间的分子相互作用。这些研究将使用SARS 2病毒样颗粒进行。分子动力学模拟的结果将为实验结果提供一个解释性的框架。这个RAPID奖是由分子和细胞生物科学部的细胞动力学和功能项目颁发的，使用的资金来自冠状病毒援助，救济，经济安全（CARES）该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准。