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

病毒感染是世界各地的一个主要公共卫生问题。重要的是研究疫苗等可以消除或减少感染机会的方法。当病毒颗粒粘在活细胞的外层时，感染就开始了，大多数疫苗和疗法都是通过试图阻止病毒颗粒和细胞表面之间的粘连来发挥作用的。因此，重要的是要了解病毒颗粒是如何感染人体细胞的。在这个项目中，研究人员提议研究病毒与细胞黏附的机制。这种做法是双管齐下的。首先，将开发病毒-细胞黏附的计算机模型模拟，并用于研究病毒/细胞黏附过程的两个共同特征：(A)病毒或细胞表面上的钉状黏附突起的作用，以及(B)病毒穿透保护细胞表面涂层的机制：糖衣。其次，计算机模型将通过附着力的实验测量来验证。该研究项目的多学科和协作性质将为研究生和本科生提供极好的教育和培训机会。调查人员将与负责公平和社区事务的副总裁合作，通过利哈伊在国家创业板联盟的机构成员资格寻找代表不足的少数族裔研究生，其使命是使代表不足的少数族裔研究生能够在STEM学科中接受教育。通过与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非正式教育活动向公众传播，内容涉及病毒、它们如何感染人类细胞以及疫苗或疗法如何起作用。该项目的目标是开发中尺度粗粒(CG)模型来研究病毒-细胞黏附过程的两个共同特征：(1)装饰在细胞膜外表面的无处不在的糖萼；(2)病毒表面(如SARS-CoV-2)或细胞膜(如埃博拉病毒)上的棘状突起，形成灵活的受体，从而调节黏附。CG方法被用来有效地在高度抽象的连续介质模型的一般性和高度详细的全原子分子模拟的特殊性之间进行优化。研究旨在回答两个相关的令人困惑的问题：(1)糖基化在介导病毒-细胞黏附中的作用是什么？具体地说，当糖萼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？以及(2)钉状突起的物理属性，如其长度和灵活性，起什么作用，以及这些属性如何影响粘附性？模型将得到验证，并伴随着在Johnson-Kendall-Roberts框架内使用AFM力谱和粘着接触力学对附着力进行实验研究。主要成果将是一套经过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特性对病毒-细胞黏附的影响。由于这两个因素存在于导致人类感染的许多病毒中，研究结果将产生广泛的社会影响。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.