Influence of the nasal microbiome on host susceptibility and response to respiratory viruses

鼻腔微生物组对宿主对呼吸道病毒的易感性和反应的影响

• 批准号: 10595400
• 负责人: Cindy Liu
• 金额: $ 75.95万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-17 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595400
• 关键词: 2019-nCoV; Acute; Address; Adult; Affect; Bacteria; Child; Chronic; Coculture Techniques; Communicable Diseases; Communities; Coronavirus; Disease; Environment; Epidemiology; Epithelium; FluMist; Goals; Home; Homeostasis; Immune; Immune response; Immunology; In Vitro; Infant; Infectious Diseases Research; Inflammation; Inflammatory; Influenza; Influenza A virus; Interferons; Knowledge; Longitudinal Studies; Lower respiratory tract structure; Mission; Modeling; Mucous Membrane; Mucous body substance; Nasal cavity; Nose; Outcome; Population; Predisposition; Property; Public Health; Research; Respiratory System; Respiratory Tract Infections; Rest; Rhinovirus; Risk; Risk Reduction; Sampling; Testing; Time; United States National Institutes of Health; Upper respiratory tract; Vaccination; Variant; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; Work; airway epithelium; cytokine; disorder risk; experimental study; host-microbe interactions; improved; innovation; microbiome; microbiome composition; nasal microbiome; novel strategies; prevent; respiratory microbiome; respiratory virus; response; virology

PROJECT SUMMARY The nasal cavity has a unique microbiome, which is expected to significantly affect local immune response and in turn, susceptibility of the host to respiratory viruses. However, we know little about these potential host- microbe interactions. Our long-term goal is to elucidate how microbiome-immune interactions and dynamics within the nasal cavity affect host susceptibility to infectious and inflammatory conditions. This project’s objective is to determine natural dynamics of correlations between nasal microbiome and local immune environment and how this relationship affects host susceptibility to respiratory viral infections. Our central hypothesis is that during homeostasis, the nasal microbiome impacts local antiviral immune defenses, including epithelial integrity, mucus properties, and antiviral cytokines and specific nasal microbiome-immune environments defined by low-inflammation and high-interferon levels will confer greater natural protection against respiratory viral infections. The rationale for this project is that our knowledge regarding the adult nasal microbiome and immune environment during homeostasis is limited. Addressing this gap can immediately improve our fundamental understanding of the adult nasal cavity and inform strategies that promote naturally occurring protection against respiratory viral infections. Aim 1. Elucidate dynamics of the homeostatic nasal microbiome and immune environment in adults. We will achieve this aim by studying (i) the homeostatic nasal microbiome and innate immune profile in a cross-section of adults (n = 400) and (ii) assessing short- and long-term dynamics of adult nasal environment by selecting and following 118 adults through monthly and quarterly dense sampling over a 12-month period. Aim 2. Determine how the nasal microbiome-immune environment affects susceptibility to an intra- nasal virus challenge. We will achieve this aim by studying how pre-vaccination nasal microbiome-immune environments impact post-vaccination viral infection and replication among adult FluMist® recipients (n = 200) per year in Years 1 and 2. Aim 3. Elucidate interactions between nasal microbiome, nasal immune environment, and host susceptibility to respiratory viruses in vitro. We will achieve this aim by assessing effect of nasal microbiome composition and nasal bacterial absolute abundance on: (i) innate immune defenses and (ii) influenza A, rhinovirus, and SARS-CoV-2 infectivity using an innovative in vitro nasal microbiome-respiratory epithelial co-culture model. The proposed research is innovative because it represents a departure from the status quo by assessing how the nasal microbiome, which is ubiquitous and diverse, could affect natural immune environment. significant because it is expected to identify nasal microbiome features and immune profiles that confer natural antiviral protection, which could inform novel strategies to reduce the risk for respiratory viral infections.

项目概要 鼻腔具有独特的微生物群，预计会显着影响局部免疫反应 反过来，宿主对呼吸道病毒的易感性。然而，我们对这些潜在的宿主知之甚少—— 微生物相互作用。我们的长期目标是阐明微生物组与免疫的相互作用和动态如何 鼻腔内的细菌会影响宿主对感染和炎症的易感性。这个项目的 目的是确定鼻腔微生物组与局部免疫之间相关性的自然动态 环境以及这种关系如何影响宿主对呼吸道病毒感染的易感性。我们的中央 假设是在体内平衡期间，鼻腔微生物群影响局部抗病毒免疫防御， 包括上皮完整性、粘液特性、抗病毒细胞因子和特定鼻微生物组免疫 由低炎症和高干扰素水平定义的环境将提供更大的自然保护 对抗呼吸道病毒感染。该项目的基本原理是我们对成人的了解 体内平衡期间的鼻微生物组和免疫环境是有限的。解决这一差距可以 立即提高我们对成人鼻腔的基本了解，并提供策略 促进自然发生的针对呼吸道病毒感染的保护。 目标 1. 阐明成人鼻腔微生物稳态和免疫环境的动态。 我们将通过研究（i）鼻腔微生物群的稳态和先天免疫特征来实现这一目标 成人横截面（n = 400）和（ii）评估成人鼻腔环境的短期和长期动态 通过在 12 个月的时间内每月和每季度进行密集抽样，选择并跟踪 118 名成年人。 目标 2. 确定鼻腔微生物组免疫环境如何影响对体内微生物的易感性 鼻病毒挑战。我们将通过研究疫苗接种前鼻腔微生物组如何免疫来实现这一目标 环境影响成年 FluMist® 接受者中疫苗接种后病毒感染和复制 (n = 200) 第一年和第二年每年。 目标 3. 阐明鼻腔微生物组、鼻腔免疫环境和宿主之间的相互作用 体外对呼吸道病毒的敏感性。我们将通过评估鼻腔治疗的效果来实现这一目标 微生物组组成和鼻腔细菌绝对丰度：(i) 先天免疫防御和 (ii) 使用创新的体外鼻微生物群-呼吸系统研究甲型流感、鼻病毒和 SARS-CoV-2 感染性 上皮共培养模型。 拟议的研究具有创新性，因为它通过评估来代表与现状的背离 无处不在且多样化的鼻腔微生物群如何影响自然免疫环境。 意义重大，因为它有望识别鼻腔微生物组特征和免疫特征，从而赋予 天然抗病毒保护，可以为降低呼吸道病毒感染风险的新策略提供参考。