Role of the Glycocalyx and Spike-Like Proteins in Virus-Cell Adhesion

糖萼和刺突状蛋白在病毒-细胞粘附中的作用

• 批准号: 2226779
• 负责人: Anand Jagota
• 金额: $ 44.7万
• 依托单位: Lehigh University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2226779&HistoricalAwards=false
• 关键词: Role; Glycocalyx; Spike; Like; Proteins

Viral infection is a major public health issue around the world. It is important to work on methods such as vaccines that can eliminate or reduce the chance of getting infected. Infections begin when a viral particle sticks to the outer coating of a live cell and most vaccines and therapies work by trying to block the adhesion between the viral particle and the cell surface. It is, therefore, important to understand how virus particles infect our body’s cells. In this project, the investigators propose to study the mechanisms of virus-cell adhesion. The approach is two-pronged. First, computer model simulations of virus-cell adhesion will be developed and used to study two common features of virus/cell adhesion processes: (a) the role of spike-like adhesive protrusions on the virus or cell surface, and (b) the mechanism by which viruses penetrate through the protective cell surface coating: the Glycocalyx. Second, the computer models will be validated by experimental measurements of adhesion. The multidisciplinary and collaborative nature of this research program will provide excellent educational and training opportunities for graduate and undergraduate students. The investigators will work with the Deputy Vice President for Equity and Community to seek under-represented minority candidates for graduate study through Lehigh’s institutional membership in the National GEM Consortium with its mission to enable underrepresented minority graduate students’ education in STEM disciplines. Via a long-standing partnership with the Da Vinci Science Center in Allentown PA, the work will be communicated to the general public through the design of new learning activities for informal education about viruses, how they infect human cells, as well as how vaccines or therapies work. The goal of the project is to develop meso-scale coarse-grained (CG) models to study two common features of virus-cell adhesion processes: (1) the omnipresent glycocalyx that decorates the exterior surface of a cell membrane, and (2) spike-like protrusions either on the viral surface (e.g., SARS-CoV-2) or on the cell membrane (e.g., Ebola) that form flexible receptors and so mediate adhesion. The CG approach is used to effectively optimize between the generality of highly abstracted continuum models and the specificity of highly detailed all-atom molecular simulations. Studies are designed to answer two related puzzling questions: (1) What is the role of the glycocalyx in mediating virus-cell adhesion? Specifically, how does the virus reach the cell-membrane-bound receptors when the glycocalyx thickness is significantly larger than the virus size? and (2) What is the role of the physical properties of spike-like protrusions, such as their length and flexibility, and how do these affect adhesion? Models will be validated and accompanied by experimental investigation of adhesion using AFM force spectroscopy and adhesion contact mechanics within the Johnson-Kendall-Roberts framework. The primary outcome will be a set of experimentally validated coarse-grained models that can be used to study and predict the effect of spike-like protrusions and glycocalyx properties on virus-cell adhesion. Because these two elements occur in so many of the viruses that cause infections in humans, the results of the studies will have broad societal impact.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.

病毒感染是全球一个主要的公共卫生问题。重要的是要处理可以消除或减少感染机会的疫苗等方法。当病毒颗粒粘在活细胞的外涂层上时，感染开始时，大多数疫苗和疗法试图阻止病毒颗粒和细胞表面之间的粘合剂。因此，重要的是要了解病毒颗粒如何感染我们人体的细胞。在这个项目中，研究人员建议研究病毒细胞粘合剂的机制。该方法是两管齐的。首先，将开发和使用计算机模型模型，用于研究病毒/细胞粘合剂过程的两个共同特征：（a）尖峰样粘合剂蛋白在病毒或细胞表面上的作用，以及（b）病毒通过受保护的细胞表面涂层穿透的机制：糖胶质分析。其次，计算机模型将通过粘附的实验测量来验证。该研究计划的多学科和协作性质将为研究生和本科生提供出色的教育和培训机会。调查人员将与股票和社区副副总裁合作，通过里海（Lehigh）在国家宝石财团中的机构成员身份寻求代表性不足的少数候选人进行研究生学习，其使命是使代表性不足的少数群体研究生在STEM学科中的教育。通过与宾夕法尼亚州Allentown的Da Vinci科学中心建立长期合作伙伴关系，将通过设计有关非正式教育的新学习活动，有关病毒，他们如何感染人类细胞以及疫苗或治疗方法的工作，通过设计新的学习活动来传达这项工作。该项目的目的是开发中尺度的粗粒（CG）模型来研究病毒细胞粘附过程的两个共同特征：（1）装饰细胞膜外表面的无所不在的糖脂，以及（2）在病毒表面上类似尖峰的突出（e.g.，sars-cov-2），E.G.，E.G.，E.受体，因此介导粘合剂。 CG方法用于有效地优化高度抽象的持续模型和高度详细的全原子分子模拟的特异性。研究旨在回答两个相关的难题问题：（1）糖蛋白在介导病毒细胞粘合剂中的作用是什么？具体而言，当糖蛋白厚度明显大于病毒大小时，病毒如何到达细胞膜结合的受体？ （2）尖峰样蛋白的物理特性（例如其长度和柔韧性）的作用是什么？这些作用如何影响粘合剂？通过使用AFM力光谱和Johnson-Kendall-Roberts框架内的AFM力光谱和粘合剂接触力学对粘合剂进行实验研究，将通过对粘合剂进行实验研究来验证模型。主要结果将是一组经过实验验证的粗粒模型，可用于研究和预测尖峰样蛋白和糖脂特性对病毒细胞粘合剂的影响。由于这两个元素发生在许多引起人类感染的病毒中，因此研究结果将产生广泛的社会影响。该奖项反映了NSF的法定任务，并通过使用基金会的智力优点和更广泛的影响来审查标准，被视为通过评估来获得支持。