Modulation of Lung Immune Responses to Viral Infection

项目总结/摘要 我们建议在杰克逊实验室（JAX CCHI）建立一个U19人类免疫学合作中心， 阐明先天免疫网络，形成适应性免疫反应，呼吸道病毒感染， 人类的肺上皮屏障位于宿主和环境之间的界面，在那里它们感觉到入侵 病原体树突状细胞（Dendritic cells，DC）将病原体来源的抗原呈递给T和B细胞以诱导免疫应答。 然而，人肺组织环境对DC和其他细胞的影响，如新发现的 先天性淋巴样细胞（ILC）家族以及细菌反应性MAIT细胞尚未完全了解。一个 研究不足的环境因素是肺部微生物组。已知微生物群会严重调节 免疫细胞的功能，特别是在粘膜表面，但这是如何发生在肺没有完全解决。 JAX CCHI试图使用多学科实验来解决这些关键问题。 这种方法将免疫学与上皮细胞生物学沿着与基因组，细胞， 在人肺组织中鉴定的功能和微生物组参数。我们的首要假设是 粘膜T细胞对呼吸道病毒感染的应答的质量和程度由交叉- 微生物群、上皮细胞和白细胞之间的对话。为了解决这个假设，我们构造了JAX CCHI 围绕两个综合研究项目，重点研究肺抗病毒免疫的基本免疫学机制; 这是一个技术开发项目，将利用3D生物打印、基因 编辑工具和微生物组免疫测定，以支持项目目标;用于存储和 人体组织的分布;以及用于专门微生物组分析、培养和 计算分析我们的中心将汇集临床医生和肺部免疫学专家， 微生物组，生物工程，基因组学和计算生物学，以实现我们的目标，并最大限度地 这项研究的潜力。行政核心将为 程序.本CCHI的目标是：1）了解上皮细胞和免疫细胞的网络是如何在 人肺调节对呼吸道病毒的先天性和适应性免疫; 2）定义炎症如何驱动 由微生物组决定组织的稳定状态，即，免疫设定点; 3）确定是否以及如何免疫 在两种肺部疾病中，儿童哮喘和成人肺癌， 对公共卫生的影响; 4）开发创新技术，模拟人类肺部免疫动力学， 阐明肺抗病毒反应的分子机制、细胞类型和关键途径。影响：通过 我们的研究集中在人肺中抗病毒免疫的传感器、诱导剂和调节剂，我们的CCHI将 贡献的见解，可以帮助改善结果的传染病和其他免疫疾病，起源于 或继发性地影响肺部。

PROJECT SUMMARY/ABSTRACT OVERALL We propose a U19 Cooperative Center on Human Immunology at The Jackson Laboratory (JAX CCHI) to elucidate the innate immune networks that shape adaptive immune responses to respiratory viral infections in the human lung. Epithelial barriers lie at the interface between host and environment, where they sense invading pathogen. Dendritic cells (DCs) present pathogen-derived antigens to T and B cells to induce immune responses. However, the impact of the human lung tissue environment on DC and other cells, such as the newly identified innate lymphoid cell (ILC) family, as well as bacteria-reactive MAIT cells, is not completely understood. An understudied environmental factor is the lung microbiome. Microbiota are known to critically modulate the function of immune cells, particularly at mucosal surfaces, but how this occurs in the lung is not fully addressed. The JAX CCHI seeks to address these critical questions using a multi-disciplinary experimental approach that will integrate immunology with epithelial cell biology along with genomic, cellular, functional and microbiome parameters identified in human lung tissues. Our overarching hypothesis is that the quality and magnitude of mucosal T cell responses to respiratory viral infections are determined by the cross- talk between microbiota, epithelial cells and leukocytes. To address this hypothesis, we structured the JAX CCHI around two integrated research projects focused on basic immunological mechanisms of lung antiviral immunity; a technology development project that will create sophisticated cellular models leveraging 3D bioprinting, gene editing tools and microbiome-immune assays to support project objectives; a sample core for storage and distribution of human tissues; and a microbiome core for specialized microbiome profiling, cultivation, and computational analysis. Our Center will bring together clinicians with experts in lung immunology, the microbiome, bioengineering, genomics and computational biology to achieve our goals and maximize the potential of this research. An administrative core will provide coordination, communication and oversight for the program. The goals of this CCHI are to: 1) Understand how the networks of epithelial cells and immune cells in the human lung regulate innate and adaptive immunity to respiratory viruses; 2) Define how inflammation driven by the microbiome dictates the steady state of tissue, i.e., immune set-point; 3) Determine if and how this immune set-point is altered in two pulmonary diseases, childhood asthma and adult lung cancer, which have a major impact on public health; and 4) Develop innovative technologies to model human lung-immune dynamics and elucidate molecular mechanisms, cell types and pathways key to lung antiviral responses. Impact: Through studies focused on the sensors, inducers and modulators of antiviral immunity in the human lung, our CCHI will contribute insights that could help improve outcomes for infectious and other immune diseases that originate in or secondarily impact the lung.