Characterization of pathogen transport through biofluid barriers

粘膜屏障是先天性免疫系统的关键组成部分，通过与宿主内病原体的相互作用和隔离，并在传播点影响病原体的生存，从而影响疾病的传播。到目前为止，我们对病原体和粘蛋白糖蛋白(粘液的主要结构成分)之间相互作用的生物物理机制的了解还不完全。这阻碍了我们理解和模拟宿主内病原体动态的能力，特别是在感染的初始阶段，病原体必须穿越粘膜屏障，克服宿主的先天性免疫反应。它还限制了我们合理设计生物材料的能力，这些材料在隔离和中和病原体的能力上模仿粘蛋白。解决这些局限性符合我的团队的长期研究目标，即开发新的、具有生物物理学知识的病原体传播数学模型，并开发能够隔离病原体的粘蛋白模拟生物材料。实现这些目标所必需的基础科学包括确定病原体在粘膜屏障中的传输、移动和传染性。因此，本发现计划将重点了解控制病原体/粘蛋白相互作用的物理过程，以及使用病毒粒子作为模型病原体系统通过粘蛋白凝胶传输病原体的物理过程。具体的研究目标是：目标1：我们将利用实验和模拟技术来表征粘蛋白屏障对病毒和假病毒粒子迁移和运输的影响。呼吸道粘液层是呼吸道病毒感染的第一个障碍，阐明病毒与粘蛋白之间可能的相互作用对于理解和模拟感染过程的这一阶段至关重要。目的2：直接检测粘蛋白对病毒感染的影响。为此，我们将使用目标1中描述的病毒粒子，在有无粘蛋白凝胶和天然粘液的情况下进行细胞转导实验。这些结果将使我们能够直接识别允许或限制病毒运输、与细胞受体结合和进入细胞的病毒和粘蛋白的关键结构成分。这项研究将提高我们对粘蛋白(和粘膜屏障)与病原体之间的相互作用，以及这些相互作用对宿主感染早期阶段的影响的理解。这将为开发新的病原体传播的生物物理精确模型提供基础。此外，更好地了解病原体与生物分子是如何在物理化学上相互作用的，将对指导设计用于隔离病原体的生物材料的开发至关重要。重要的是，这一研究进展将与HQP在从生物流体表征到数学模型开发等领域的跨学科培训同时进行。

Mucosal barriers are key components of the innate immune system that influence disease transmission by interacting with and sequestering pathogens within-hosts and by influencing pathogen survival at the point of transmission. To date, our understanding of the biophysical mechanisms governing interactions between pathogens and mucin glycoproteins, the primary structural components of mucus, remains incomplete. This hinders our ability to understand and model pathogen dynamics in-host, particularly during the initial stages of infection where causative pathogenic agents must traverse mucosal barriers and overcome host innate immune responses. It also limits our ability to rationally design biomaterials that mimic mucins in their ability to sequester and neutralize pathogens. Addressing these limitations aligns with the long-term research objectives of my team, namely to develop novel, biophysically informed mathematical models for pathogen spread and to develop mucin-mimetic biomaterials capable of sequestering pathogens. The foundational basic science necessary to achieve these objectives involves characterizing the transport, mobility, and infectivity of pathogens in mucosal barriers. Therefore, this Discovery program will focus on understanding the physical processes that govern pathogen/mucin interactions and the transport of pathogens through mucin gels using virions as a model pathogen system. The specific research aims are: Aim 1: We will characterize the effect of mucin barriers on the mobility and transport of viruses and pseudovirions using both experimental and modeling techniques. The mucus layer lining the respiratory tract presents a first obstacle to respiratory viruses for establishing infection, and elucidating possible virus-mucin interactions will be crucial for understanding and modeling this stage of the infection process. Aim 2: We will directly measure the effect of mucins on viral infection. To do so, we will perform cell transduction experiments in the presence and absence of mucin gels and native mucus, using the virions described in Aim 1. These results will allow us to directly identify key structural components of viruses and mucins that permit or restrict viral transport, binding to cellular receptors, and entry into cells. This research will improve our understanding of interactions between mucins (and mucosal barriers) and pathogens, and the effect of these interactions on the early stages of host infection. This will provide the basis for the development of novel biophysically accurate models for pathogen spread. Additionally, an improved understanding of how pathogens interact physiochemically with biological molecules will be critical in guiding the development of biomaterials designed to sequester pathogens. Importantly, this research progress will proceed concurrently with the interdisciplinary training of HQP in areas ranging from biological fluid characterization to mathematical model development.