Characterization of pathogen transport through biofluid barriers

病原体通过生物流体屏障运输的表征

• 批准号: RGPIN-2022-03617
• 负责人: Wagner, Caroline
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744461
• 关键词: Characterization; pathogen; transport; through; biofluid

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.

粘膜屏障是先天免疫系统的关键组成部分，它通过与宿主内部和隔离病原体相互作用并影响传播时的病原体存活来影响疾病的传播。迄今为止，我们对病原体与粘蛋白糖蛋白之间相互作用的生物物理机制（粘液的主要结构成分）仍然不完整。这阻碍了我们在宿主中理解和建模病原体动力学的能力，尤其是在感染的初始阶段，在感染的初始阶段必须穿越粘膜屏障并克服宿主的先天免疫反应。它还限制了我们合理设计生物材料的能力，使粘蛋白模仿其隔离和中和病原体的能力。 解决这些局限性与我团队的长期研究目标相吻合，即开发用于病原体传播的新颖，生物物理知识的数学模型，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涉及表征粘膜屏障中病原体的运输，流动性和感染性。因此，该发现程序将专注于理解使用病原体作为模型病原体系统的病原体/粘蛋白相互作用的物理过程以及通过粘蛋白凝胶传输的物理过程。具体的研究目的是：目标1：我们将使用实验和建模技术来表征粘蛋白屏障对病毒和伪流的迁移率和运输的影响。内衬呼吸道的粘液层为建立感染的呼吸道病毒带来了第一个障碍，阐明可能的病毒粘膜相互作用对于理解和建模感染过程的这一阶段至关重要。目标2：我们将直接测量粘蛋白对病毒感染的影响。为此，使用AIM 1中描述的病毒粒子，我们将在存在和不存在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转运的病毒和粘液的关键结构成分，从而与细胞受体结合并进入细胞。这项研究将提高我们对粘蛋白（和粘膜屏障）和病原体之间相互作用的理解，以及这些相互作用对宿主感染的早期阶段的影响。这将为开发新型生物物理精确模型的病原体扩散模型提供基础。此外，对病原体在物理化学上与生物分子的相互作用的改进了解对于指导旨在隔离病原体的生物材料的发展至关重要。重要的是，这项研究的进步将与HQP的跨学科培训同时进行，范围从生物流体表征到数学模型开发。