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 呼吸综合病毒（RSV）是全球主要的呼吸病原体。严重的急性呼吸道 综合征冠状病毒2（SARS-COV-2）大流行导致了前所未有的危机。呼吸道病毒 感染通常伴有胃肠道（GI）症状，但呼吸道病原体如何引起GI 疾病尚不清楚。此外，正在开发许多疫苗和疗法 但是，重要的病原体并未概括人类的经验。小动物和 非人类灵长类动物模型缺少模仿人类疾病，人类RSV挑战模型是 昂贵并引起了安全问题。 BSL-3设施研究SARS-COV-2 HAMPERS数据的要求 产生并增加成本。人类内在cov-nl63可以用作SARS-COV-2的代理 它使用相同的宿主受体，血管紧张素转换酶2。 通过推进我们当前的3维（3D）鼻/肺模型来进行挑战气道模型 RSV和COV-NL63（SARS-COV-2的代理），以解决急需的临床前模型的需求 概括人类疾病。与人类仿生科学核心合作，我们有 开发了用于隔离茎细胞并从鼻腔产生3D鼻和肺器官线的专业知识 分别洗涤和支气管肺泡液。我们在RSV和其他方面的国际认可的专业知识 呼吸道病毒独特地定位了我们开发高级3D鼻子/肺模型，以剖析 RSV的发病机理（AIM 1），并使用工程微环境开发气道和GI平台 核心（EMEC）评估驱动呼吸道病毒疾病肺轴的分子机制（AIM 2）。 我们将根据性别和年龄选择捐助者，以便我们可以全面研究 宿主（年龄，性别，独特的气道站点和免疫电池）和病毒，以及体液和细胞的贡献 HLA限制系统中的免疫反应。我们还将通过研究 RSV和COV-NL63气道感染对GI区域的下游影响通过直接（感染）或间接 （炎症）使用肺肠流系统的途径。该项目通过开发对RFA敏感 高级鼻子/肺模型的复杂性增加，包括体液和细胞免疫， 在呼吸道病毒疾病的肺轴轴上定义了新的机械途径。全球科学 社区将从3D鼻子/肺气道病毒模型中受益匪浅，该模型概括了人类病毒 感染并用作评估治疗和疫苗的平台。