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：
10579867
负责人：
Anna Karolina Palucka
金额：
$ 87.1万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-05 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579867
关键词：
3D Print Affect Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Response Apoptotic Autoimmunity Bacteria CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell physiology Cells Chromatin Clinical Cross Presentation DNA Dendritic Cells Development Dissociation Effector Cell Environment Enzymes Epithelial Cells Experimental Genetics Exposure to Fc Receptor Functional disorder Future Generations Genetic Transcription Goals Harvest Human Immune Immunity In Situ In Vitro Infection Inflammation Inflammatory Response Influenza A Virus, H1N1 Subtype Invaded Label Laboratories Link Lung Lung Capacity Lung immune response Macrophage Malignant Neoplasms Mediating Molecular Mucous Membrane Myeloid Cells Nature Neoplastic Processes Oral cavity Outcome Pathogenesis Pathway interactions Phenotype Predisposition Pulmonary Inflammation RNA Viruses Regulation Research Research Project Grants Research Project Summaries Resistance Resolution Respiratory Tract Infections Role Signal Transduction Specificity Stains Structure of parenchyma of lung Systemic Lupus Erythematosus T cell differentiation T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Tropism Upper respiratory tract Vaccines Validation Viral Viral Antigens Viral Proteins Viral Respiratory Tract Infection Virus Virus Diseases Work adaptive immune response adaptive immunity alveolar epithelium antiviral immunity commensal bacteria design draining lymph node functional status human tissue immunological status improved influenzavirus microbiome novel pandemic disease pathogen permissiveness programs receptor expression resistance gene respiratory virus response viral resistance

项目摘要

PROJECT SUMMARY RESEARCH PROJECT 1 Project 1 will elucidate how the networks of antigen presenting cells (APCs) in the human lung regulate immunity to respiratory viruses. The goal is to also explain how microbiome-driven lung inflammation or inflammation that is linked with neoplastic processes affects such responses. Project 1 is founded on the scientific premise that identifying the pathways underpinning immune cell responses to respiratory viruses in situ is key to identifying targets and strategies for designing and developing improved vaccines. Our overall hypothesis is that the lung environment defines immunological status, i.e., the “immune set-point”, and the function of tissue-resident dendritic cells (DCs). We further posit that the immune set-point impacts the fate of antigen and the quality and magnitude of ensuing mucosal T-cell immunity. Implicit in this hypothesis is a role for the local microbiome, which we predict contributes to the immediate environment by direct and indirect crosstalk with immune cells and ensuing inflammatory responses. We propose three aims: Aim 1 will test the hypothesis that steady state cellular and molecular networks in human lung tissue regulate the early response to respiratory viruses. We will define the composition and functional status of human lung tissue across a range of clinical situations: normal lung, uninvolved cancer patient lung and cancer-involved lung tissue. Correlative analyses with upstream environmental regulators such as the microbiome will identify pathways that control the magnitude and quality of ensuing adaptive immunity. Aim 2 will test the hypothesis that the generation of anti-viral T-cell immunity is modulated by lung epithelial cell (EC)-DC crosstalk and that this crosstalk is further modulated by commensal bacteria. We will determine how lung DCs exposed to virally-infected lung alveolar epithelial cells (AECs) modulate the differentiation of T cells; we will establish the molecular programs in DCs triggered by lung ECs that can explain T-cell phenotypes; and we will determine how the bacteria cultured from the mouth and upper respiratory tract impacts lung ECs and downstream responses. Aim 3 will test the hypothesis that the lung microenvironment modulates the cross-presentation capacity of lung-resident APCs thereby dictating the fate of viral antigen-specific CD8+ T cells. We will assess viral distribution and cross-presentation in the context of resistant and susceptible cells defined by expression of a viral resistance gene, Rab15; and the access of opsonized virus to cross-presenting compartments in lung myeloid cells. Thus, this project will elucidate the key innate immune networks that determine the overall outcome of adaptive immune responses during respiratory viral infections. Along with other Projects, our proposed research has a high potential to discover novel target molecules that will eventually help us design improved therapeutics and vaccines for respiratory infections. Finally, the work proposed here will guide development and validation of 3D printed lung tissues, which will enable genetic experiments and possibly future studies on human tissue immunity.

项目概要研究项目 1 项目 1 将阐明人肺中的抗原呈递细胞 (APC) 网络如何调节免疫其目标还在于解释微生物组驱动的肺部炎症或炎症如何影响呼吸道病毒。与肿瘤过程影响此类反应有关，项目 1 的科学前提是：原位识别支持免疫细胞对呼吸道病毒反应的途径是识别的关键设计和开发改进疫苗的目标和策略我们的总体假设是肺部。环境定义了免疫状态，即“免疫设定点”，以及组织驻留的功能我们进一步假设免疫设定点影响抗原的命运和质量。该假设隐含了局部微生物组的作用，即粘膜 T 细胞免疫的强度。我们预测通过与免疫细胞的直接和间接串扰对周围环境做出贡献我们提出了三个目标：目标 1 将检验稳态细胞的假设。我们将定义人体肺组织中的分子网络调节对呼吸道病毒的早期反应。人类肺组织在一系列临床情况下的组成和功能状态：正常肺，未涉及的癌症患者肺和涉及癌症的肺组织与上游的相关分析。微生物组等环境调节剂将确定控制规模和质量的途径目标 2 将检验抗病毒 T 细胞免疫的产生是的假设。由肺上皮细胞（EC）-DC 串扰调节，并且该串扰进一步由共生体调节我们将确定肺 DC 如何暴露于病毒感染的肺泡上皮细胞 (AEC)。调节T细胞的分化；我们将建立由肺EC触发的DC分子程序这可以解释 T 细胞表型；我们将确定细菌是如何从口腔和上颌培养的呼吸道影响肺 EC 和下游反应，目标 3 将检验肺的假设。微环境调节肺驻留 APC 的交叉呈递能力，从而决定 APC 的命运我们将评估病毒抗原特异性 CD8+ T 细胞的背景。通过病毒抗性基因 Rab15 的表达和获取来定义抗性和易感细胞；因此，该项目将阐明关键的关键。先天免疫网络决定呼吸过程中适应性免疫反应的总体结果与其他项目一样，我们提出的研究很有可能发现新的靶点。最终将帮助我们设计改进的呼吸道感染疗法和疫苗的分子。最后，这里提出的工作将指导 3D 打印肺组织的开发和验证，这将实现基因实验以及未来可能对人体组织免疫的研究。