Human Airway Biomimetics for RSV and Other Respiratory Viruses

RSV 和其他呼吸道病毒的人体气道仿生学

• 批准号: 10192209
• 负责人: Pedro A Piedra
• 金额: $ 35.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10192209
• 关键词: 2019-nCoV; 3-Dimensional; ACE2; Address; Adult; Advanced Development; Age; Air; Animal Model; Animals; Apical; Automobile Driving; Biomimetics; Blood Circulation; Bronchoalveolar Lavage; COVID-19 pandemic; COVID-19 vaccine; Cells; Cellular Immunity; Child; Childhood; Clinical Trials; Coculture Techniques; Collaborations; Communities; Complex; Data; Deglutition; Development; Disease; Disease Pathway; Engineering; Female; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Heparan Sulfate Proteoglycan; Human; Humoral Immunities; Immune; Immune response; Immunity; Infection; Inflammation; Innate Immune Response; International; Intestines; Kinetics; Liquid substance; Lung; Lung diseases; Modeling; Molecular; Mucous Membrane; Nasal Epithelium; Nose; Organoids; Pathogenesis; Pathway interactions; Positioning Attribute; Pre-Clinical Model; Proxy; Research; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; SARS-CoV-2 infection; Safety; Site; Study models; System; Therapeutic; Time; Tropism; Vaccines; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; adaptive immune response; airway epithelium; base; biosafety level 3 facility; cost; cytokine release syndrome; experience; falls; gastrointestinal; gastrointestinal symptom; gastrointestinal system; gut-lung axis; human disease; immunoprophylaxis; injured airway; male; neutralizing antibody; nonhuman primate; novel; pathogen; receptor; respiratory; respiratory infection virus; respiratory pathogen; respiratory virus; sex; stem cells; vaccine candidate; vaccine evaluation

PROJECT SUMMARY – Project 2 Respiratory syncytial virus (RSV) is a major global respiratory pathogen. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has resulted in an unprecedented crisis. Respiratory virus infections are often accompanied by gastrointestinal (GI) symptoms, but how respiratory pathogens cause GI disease is not understood. Moreover, a number of vaccines and therapeutics are being developed against these important pathogens, however, the existing models do not recapitulate the human experience. Small animal and non-human primate models fall short of mimicking human disease, and the human RSV challenge model is expensive and raises safety concerns. The requirement for BSL-3 facilities to study SARS-CoV-2 hampers data generation and increases cost. The human endemic CoV-NL63 can serve as a proxy for SARS-CoV-2 because it uses the same host receptor, angiotensin-converting enzyme 2. This project will develop an ex-vivo Human Challenge Airway Model by advancing our current 3-dimensional (3D) nose/lung model for studies on RSV and CoV-NL63 (proxy for SARS-CoV-2) to address the urgent need for a preclinical model that recapitulates the human disease. In collaboration with the Human Biomimetic Scientific Core, we have developed the expertise for isolating stems cells and generating 3D nose and lung organoid lines from nasal wash and bronchoalveolar fluids, respectively. Our internationally recognized expertise in RSV and other respiratory viruses uniquely positions us to develop advanced 3D nose/lung models for dissecting the pathogenesis of RSV (Aim 1), and develop airway and GI platforms with the Engineering Micro-Environment Core (EMEC) to evaluate molecular mechanisms driving the lung-gut axis of respiratory virus disease (Aim 2). We will select donors based on sex and age so that we can comprehensively study the complex interactions of host (age, sex, distinct airway sites, and immune cells) and virus, and the contribution of humoral and cellular immune responses in an HLA-restricted system. We will also evaluate the lung-gut axis by studying the downstream effects of RSV and CoV-NL63 airway infection on the GI tract by either direct (infection) or indirect (inflammation) pathways using lung-gut flow systems. This project is responsive to the RFA by the development of an advanced nose/lung model with increased complexity that includes humoral and cellular immunity, as well as defining novel mechanistic pathways in the lung-gut axis of respiratory virus disease. The global scientific community will benefit immensely from a 3-D nose/lung airway-virus model that recapitulates human virus infection and serves as a platform to evaluate therapeutics and vaccines.

项目摘要 – 项目 2 呼吸道合胞病毒（RSV）是全球主要的呼吸道病原体。 综合症冠状病毒 2 (SARS-CoV-2) 大流行导致了前所未有的呼吸道病毒危机。 感染通常伴有胃肠道 (GI) 症状，但呼吸道病原体如何引起胃肠道症状 此外，针对这些疾病的许多疫苗和疗法正在开发中。 然而，现有的模型并不能概括人类和小动物的经验。 非人类灵长类动物模型无法模拟人类疾病，而人类 RSV 挑战模型 研究 SARS-CoV-2 所需的 BSL-3 设施成本高昂并引发安全问题。 人类地方性 CoV-NL63 可以作为 SARS-CoV-2 的替代品，因为 它使用相同的宿主受体，血管紧张素转换酶2。该项目将开发一种离体人类 通过推进我们当前的 3 维 (3D) 鼻/肺模型来研究以下问题，从而挑战气道模型 RSV 和 CoV-NL63（SARS-CoV-2 的替代品）可满足临床前模型的迫切需求 我们与人类仿生科学核心合作，概括了人类疾病。 开发了分离干细胞并从鼻腔生成 3D 鼻和肺类器官线的专业知识 我们分别在 RSV 和其他领域获得国际公认的专业知识。 呼吸道病毒使我们能够开发先进的 3D 鼻/肺模型来解剖呼吸道病毒 RSV 的发病机制（目标 1），并利用工程微环境开发气道和胃肠道平台 核心 (EMEC) 评估驱动呼吸道病毒疾病肺肠轴的分子机制（目标 2）。 我们会根据性别和年龄来选择捐赠者，以便我们能够全面研究捐赠者之间复杂的相互作用。 宿主（年龄、性别、不同气道部位和免疫细胞）和病毒，以及体液和细胞的贡献 我们还将通过研究 HLA 限制系统中的免疫反应来评估肺肠轴。 RSV 和 CoV-NL63 气道感染通过直接（感染）或间接对胃肠道产生下游影响 使用肺-肠流系统的（炎症）途径该项目通过开发响应 RFA。 先进的鼻/肺模型的复杂性增加，包括体液和细胞免疫，以及 定义了呼吸道病毒疾病肺肠轴的新机制途径。 社区将从再现人类病毒的 3D 鼻/肺气道病毒模型中受益匪浅 感染并作为评估治疗方法和疫苗的平台。