Modulation of Viral Antigen Presentation in the Lung

肺部病毒抗原呈递的调节

基本信息

批准号：
10436633
负责人：
Anna Karolina Palucka
金额：
$ 49.83万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-02 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436633
关键词：
2019-nCoV 3-Dimensional Acute Address Administrative Supplement Adult Affect Age Alternative Splicing Antigen Presentation Antigens Antiviral Response Autoimmune Diseases Award B-Lymphocytes Bacteria Biology Biomedical Engineering Blood Cells COVID-19 COVID-19 patient Cell Line Cell model Cell physiology Cells Cellular biology Child Childhood Childhood Asthma Clinical Code Cohort Effect Communication Complement Complex Computational Biology Computer Analysis Coronavirus Data Set Dendritic Cells Dimensions Disease Environment Environmental Risk Factor Epithelial Epithelial Cells Family Funding Future Generations Genes Genetic Transcription Genomics Goals Human Immune Immune System Diseases Immune response Immune system Immunologics Immunology Immunology procedure Individual Infant Infection Inflammation Influenza Interferon Type I Interferons Interleukin-1 Invaded Leukocytes Long COVID Lung Lung diseases Lymphocyte Lymphoid Cell Malignant neoplasm of lung Messenger RNA Molecular Mucous Membrane Natural Immunity Parents Pathway interactions Patients Pediatric cohort Peptides Peripheral Peripheral Blood Mononuclear Cell Phenotype Production Protein Isoforms Proteins Proteomics Public Health RNA RNA Splicing Recording of previous events Research Research Project Grants Respiratory syncytial virus Ribonucleoproteins SARS-CoV-2 infection Sampling Severity of illness Shapes Small Nuclear RNA Specificity Spliceosomes Structure Structure of parenchyma of lung Surface Systemic Lupus Erythematosus T cell response T-Lymphocyte Technology The Jackson Laboratory Tissues Transcript Vaccines Viral Antigens Viral Load result Viral Respiratory Tract Infection Virus Virus Diseases Work adaptive immune response adaptive immunity antiviral immunity base bioprinting cell type cohort comorbidity coronavirus disease design detection method follow-up human model human tissue immune activation immune function imprint improved outcome influenzavirus innovative technologies insight lung microbiome mRNA Precursor mRNA sequencing microbiome microbiota monocyte multidisciplinary novel pathogen pediatric patients programs proteogenomics respiratory virus response sensor single-cell RNA sequencing symptomatic COVID-19 technology development tool transcriptome transcriptome sequencing tumor virtual

项目摘要

PROJECT SUMMARY (FUNDED PARENT AWARD, U19AI142733) 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.

项目摘要（资助家长奖，U19AI142733）我们提议在杰克逊实验室 (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对呼吸道病毒感染的适应性免疫反应人的肺。上皮屏障位于宿主和环境之间的界面，在那里它们感知入侵病原。树突状细胞 (DC) 将病原体衍生的抗原呈递给 T 细胞和 B 细胞以诱导免疫反应。然而，人类肺组织环境对DC和其他细胞的影响，例如新发现的先天淋巴细胞 (ILC) 家族以及细菌反应性 MAIT 细胞尚未完全了解。一个未充分研究的环境因素是肺部微生物组。众所周知，微生物群可以严格调节免疫细胞的功能，特别是在粘膜表面，但这种情况在肺部如何发生尚未完全解决。 JAX CCHI 寻求使用多学科实验方法来解决这些关键问题，将免疫学与上皮细胞生物学以及基因组、细胞、功能和微生物组相结合在人体肺组织中确定的参数。我们的首要假设是，粘膜 T 细胞对呼吸道病毒感染的反应是由微生物群之间的相互作用决定的，上皮细胞和白细胞。为了解决这个假设，我们围绕两个集成的 JAX CCHI 构建了 JAX CCHI：研究项目侧重于肺部抗病毒免疫的基本免疫机制；一项技术开发项目将利用 3D 生物打印、基因编辑工具创建复杂的细胞模型和微生物组免疫测定以支持项目目标；用于存储和分发的样本核心人体组织；以及用于专门微生物组分析、培养和计算的微生物组核心分析。我们的中心将汇集临床医生和肺免疫学、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发挥其潜力研究。行政核心将为该计划提供协调、沟通和监督。这本 CCHI 的目标是： 1) 了解人肺中上皮细胞和免疫细胞的网络如何调节对呼吸道病毒的先天和适应性免疫； 2) 定义炎症是如何驱动的微生物组决定组织的稳态，即免疫设定点； 3）确定这种免疫是否以及如何设置- 儿童哮喘和成人肺癌这两种肺部疾病的点发生了改变，这产生了重大影响关于公共卫生； 4) 开发创新技术来模拟人类肺免疫动力学并阐明肺部抗病毒反应的关键分子机制、细胞类型和途径。影响：通过研究我们的 CCHI 专注于人肺抗病毒免疫的传感器、诱导剂和调节剂，将做出贡献有助于改善源自或起源的传染病和其他免疫疾病的见解其次影响肺部。