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.

病毒感染是世界各地的一个主要公共卫生问题。重要的是要研究疫苗等方法，以消除或减少感染的机会。 感染开始时，病毒颗粒粘在活细胞的外壳上，大多数疫苗和疗法通过试图阻止病毒颗粒和细胞表面之间的粘附而起作用。因此，了解病毒颗粒如何感染我们身体的细胞是很重要的。在这个项目中，研究人员建议研究病毒-细胞粘附的机制。 这一办法是双管齐下的。 首先，将开发病毒-细胞粘附的计算机模型模拟，并用于研究病毒/细胞粘附过程的两个共同特征：（a）病毒或细胞表面上的钉状粘附突起的作用，以及（B）病毒穿透保护性细胞表面涂层的机制：糖萼。 其次，将通过粘附力的实验测量来验证计算机模型。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良好的教育和培训机会。调查人员将与平等和社区副总裁合作，通过Lehigh在国家GEM联盟中的机构成员资格，寻求代表性不足的少数民族候选人进行研究生学习，其使命是使代表性不足的少数民族研究生能够接受STEM学科的教育。 通过与位于宾夕法尼亚州阿伦敦的达芬奇科学中心的长期合作伙伴关系，这项工作将通过设计新的学习活动传达给公众，以进行有关病毒、病毒如何感染人体细胞以及疫苗或疗法如何工作的非正式教育。 该项目的目标是开发中尺度粗粒度（CG）模型，以研究病毒-细胞粘附过程的两个常见特征：（1）装饰细胞膜外表面的无所不在的糖萼，以及（2）病毒表面上的尖刺状突起（例如，SARS-CoV-2）或细胞膜上（例如，埃博拉病毒），形成灵活的受体，从而介导粘附。 CG方法被用来有效地优化高度抽象的连续模型的一般性和高度详细的全原子分子模拟的特异性之间。研究旨在回答两个相关的困惑问题：（1）糖萼在介导病毒-细胞粘附中的作用是什么？ 具体来说，当糖萼厚度明显大于病毒大小时，病毒是如何到达细胞膜结合受体的？以及（2）尖刺状突起的物理性质，如它们的长度和柔韧性，有什么作用，以及它们是如何影响粘附力的？ 模型将进行验证，并伴随着使用AFM力谱和约翰逊-肯德尔-罗伯茨框架内的粘附接触力学的粘附实验研究。主要成果将是一组实验验证的粗粒度模型，可用于研究和预测钉状突起和糖萼性质对病毒细胞粘附的影响。 由于这两种元素存在于许多导致人类感染的病毒中，因此研究结果将产生广泛的社会影响。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值进行评估而被认为值得支持。和更广泛的影响审查标准。