CAREER: Biophysical investigations of immune-mediated pathogen trapping in mucus

这项由材料研究部的生物材料项目授予北卡罗来纳大学教堂山分校的职业奖项是为了研究粘液作为抵御病毒的屏障所起的作用。粘液是一种粘弹性生物聚合物，由粘蛋白纤维组成的致密基质组成，由人体分泌。这项研究项目将结合生物工程、生物物理学和计算模型来研究粘液中抗体的保护作用。大多数感染是在粘膜表面传播的，病毒已经进化到很容易穿透粘液。然而，抗体是如何分泌到粘液中防止感染的，人们仍然知之甚少。这项研究基于这样的假设，即抗体可以通过多价和低亲和力的交联物以永久的亲和力将病毒固定在粘液中，从而阻止病毒到达靶细胞。以前的大多数研究都未能检测到粘液可能的多价粘附性捕获效应，因为这些研究试图仅测量单一抗体和粘液成分之间的低亲和力单价相互作用。为了克服以往研究的这些缺陷，本项目将以生物素包被、粘液穿透和粘液惰性的聚苯乙烯纳米颗粒为模型系统，对抗生物素免疫球蛋白-G介导的粘液捕获的效力进行量化。颗粒在粘液中扩散的数值模拟、抗体在颗粒表面的聚集以及表面结合抗体的捕获是本研究的一部分。拟议的研究有望开发出一套总括的方程式，试图预测抗体介导的捕获对广泛的病毒病原体的有效性。此外，这项研究可以阐明一种很大程度上不为人所知的人体免疫保护机制，并可能导致新疫苗的开发和针对疱疹、艾滋病毒等病毒感染的被动免疫。通过这项多学科研究，研究生和本科生将接受纳米科学、生物物理学、数学和免疫学方面的培训。此外，PI计划开发一门新的课程，重点关注粘液在健康中的作用，并将被莫尔黑德天文馆和科学中心的外展项目使用，每年接触到北卡罗来纳州的许多K-12学生。大多数感染发生在覆盖粘液的器官，如呼吸道、胃肠道等。病毒已经进化成快速通过粘液传播感染；因此，可以阻止病毒穿透粘液的方法是一个有吸引力的方法，以加强我们的身体-S对感染的防御。在这个项目中，我们将探索如何调整免疫系统，将粘液转化为对抗各种病原体的粘性网状结构，有效地将它们捕获在粘液中，并在此过程中减少感染。具体地说，该项目将制备合成纳米颗粒，这些纳米颗粒将严格量化粘液的粘性，作为病毒颗粒大小和表面特征等基本参数的函数。此外，它还将开发一套重要的方程式来预测如何预防广泛的病毒病原体。这项研究的成功结果不仅可以解释哪种免疫系统可以预防感染，还可以指导新一代疫苗的开发。由于这项研究的多学科性质，该项目将对学生进行纳米科学、生物物理学、数学和免疫学方面的培训。这位研究人员计划利用莫尔黑德天文馆和科学中心现有的推广计划，并将开发一门新的科学课程，重点是粘液在健康中的作用，将覆盖到北卡罗来纳州的许多K-12学生。这些努力预计将激励学生继续接受科学、技术、工程和数学方面的高等教育。

This Career award by the Biomaterials program in the Division of Materials Research to University of North Carolina at Chapel Hill is to investigate the role of mucus, a viscoelastic biopolymer composed of a dense matrix of mucin fibers and secreted by human body, as a barrier against virus. This research project will combine bioengineering, biophysics and computational modeling to investigate the protective role of antibodies in mucus. Most infections are transmitted at mucosal surfaces, and viruses have evolved to readily penetrate mucus. Nevertheless, how antibodies are secreted into mucus protect against infections remain poorly understood. This study is based on the hypothesis that antibodies can immobilize viruses in mucus with permanent avidity via polyvalent and low-affinity crosslinks, thereby blocking viruses from reaching target cells. Most previous studies have failed to detect possible polyvalent-adhesive trapping effects of mucus because these studies attempted to measure only the low-affinity mono-valent interactions between a single antibody and mucus constituents. To overcome these drawbacks of the previous studies, this project will focus on quantifying the potency of anti-biotin immunoglobulin-G mediated trapping by mucus using biotin-coated, mucus-penetrating and mucus-inert polystyrene-based nanoparticles as the model system. Numerical modeling of particle diffusion across mucus, accumulation of antibody on particle surface, and trapping by surface-bound antibody are parts of this research. The proposed studies are expected to develop an overarching set of equations that will attempt to predict the effectiveness of antibody-mediated trapping against a wide range of viral pathogens. In addition, this study could elucidate a largely unrecognized mechanism of immune protection of human body, and could lead to development of new vaccines and passive immunization against viral infections such as Herpes, HIV, etc. Through this multidisciplinary research, graduate and undergraduate students will receive training across nanoscience, biophysics, mathematics and immunology. Additionally, the PI plans to develop a new curriculum, focusing on the role of mucus in health, and will be used by the outreach programs at the Morehead Planetarium and Science Center to reach out to many K-12 students in North Carolina every year.Most infections take place in organs coated with mucus, such as the airways, gastrointestinal tract, etc. Viruses have evolved to quickly move through mucus to infect; thus, methods that can block viruses from penetrating mucus represents an attractive approach to reinforce our body?s defense against infections. In this project, we will explore how the immune system can be tuned to transform mucus into a sticky mesh against diverse pathogens, effectively trapping them in mucus and reducing infections in the process. Specifically, this project will prepare synthetic nanoparticles that will rigorously quantify the stickiness of mucus as a function of basic parameters such as virus particle size and surface characteristics. In addition it will develop an overarching set of equations to predict how one could protect against a wide range of viral pathogens. A successful outcome of this research could not only explain with which immune system can protect against infections, but also could guide in the development of new generations of vaccines. Due to the multidisciplinary nature of this research, the project will train students across nanoscience, biophysics, mathematics and immunology. The researcher plans to leverage existing outreach programs at the Morehead Planetarium and Science Center, and will develop a new science curriculum focusing on the role of mucus in health that will reach many K-12 students in North Carolina. These efforts are expected to motivate students to pursue higher education in Science, Technology, Engineering, & Mathematics.