Mechanisms of vaccine immunity against coccidioidomycosis

球孢子菌病疫苗免疫机制

基本信息

批准号：
10584260
负责人：
BRUCE Steven KLEIN
金额：
$ 53.58万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584260
关键词：
Ablation Address Antigen-Presenting Cells Antigens Attenuated Vaccines Black Populations Blastomyces dermatitidis CD4 Positive T Lymphocytes CYP21A2 gene Calcineurin Canis familiaris Cell Shape Cells Cellular Immunity Coccidioides Coccidioidomycosis Data Disease Early Mobilizations Elements Emerging Communicable Diseases Epithelial Cells Epithelial Receptor Cell Epithelium Filipino Genes Genetic Polymorphism Hispanic Populations Human Immunity Immunodominant Antigens Infection Inflammatory Inflammatory Response Inhalation Kinetics Knowledge Label Link Lung Lymphocyte Lymphoid Tissue M cell Measures Mediating Memory Methods Microbe Military Personnel Morbidity - disease rate Mucosal Immunity Mucous Membrane Mus Mycoses Myelogenous Myeloid Cells NF-kappa B Natural Immunity PLCG2 gene PPP3R1 gene Patients Peptides Peyer&apos s Patches Phenotype Pregnant Women Prevention Process Reagent Reporting Reproduction spores Research Resistance Respiratory Mucosa Role Route Signal Pathway Signal Transduction Structure of parenchyma of lung Subunit Vaccines Surface T-Cell Development T-Lymphocyte Testing Tissues Training Transgenic Mice Translating United States National Institutes of Health Vaccination Vaccines Work adaptive immunity commercialization cytokine dectin 1 draining lymph node fungus infection rate innovation memory CD4 T lymphocyte mortality mucosal vaccine next generation novel pathogen priority pathogen receptor recruit response tool trafficking transcriptome uptake vaccine delivery vaccine trial

项目摘要

ABSTRACT Coccidioidomycosis is a re-emerging infection that NIH has prioritized for vaccine prevention. An experimental vaccine of live attenuated spores is highly protective after intranasal delivery. We propose to study this vaccine to define mechanisms by which lung epithelium regulates durable mucosal T cell immunity. Resistance against inhaled microbes is thought to reside within tissue-resident memory (TRM) cells, but little is known about how this intranasal vaccine induces lung TRM. Our preliminary data reveal that the vaccine elicits protective, Coccidioides endoglucanase 2 (C-Eng2) specific CD4+ T cells and that bronchiolar club cells and Ca++ calcineurin signaling in the cells are needed to mobilize inflammatory and T cells in response to vaccine. We also find that Microfold (M) cells descend from the bronchiolar club cells and facilitate T cell priming in response to the vaccine. From these preliminary data, we hypothesize that bronchiolar club cells and M cells regulate mucosal cellular immunity in response to intranasal vaccine. To test this hypothesis, we have created innovative tools: (i) transgenic mice to deplete epithelial cell subsets or their products to further define their role in inducing immunity; (ii) C-Eng2 specific tetramers to track and analyze protective CD4+ T cells and TRM in C57BL6 mice; and (iii) methods to isolate and culture human lung epithelial cells to translate results from mice to humans. We propose three aims to test our hypothesis. In Aim 1, we will elucidate early stages of the inflammatory response to intranasal vaccine regulated by bronchiolar club cells and M cells; in Aim 2, we will identify lung epithelial cell receptors - dectin-1, DUOX1 and DUOXA1 - and downstream PLCG2 that may sense intranasal vaccine and signal via Ca++ and calcineurin to mobilize mucosal immunity; and in Aim 3, we will define mechanisms of vaccine-induced durable mucosal immunity by studying lung TRM and the regulatory role of lung epithelium. In sum, we address the unmet need of vaccination against coccidioidomycosis. Our work is significant as it will define mechanisms by which a promising vaccine establishes T cell immunity at the lung mucosa. Results will identify tactics useful for other vaccine immunogens given intranasally, including subunit vaccines. The work will define correlates of immunity needed to advance this attenuated vaccine or next generation subunit vaccines against this high priority pathogen. The work will be done with state-of-the-art, cutting-edge tools. Our team of PI and Co-I’s will let us translate results from mouse to human, with tools and reagents for human lung epithelium.

抽象的球虫病术是NIH预防疫苗的重新出现的感染。实验鼻内输送后，活孢子的活孢子疫苗受到高度保护。我们建议研究这种疫苗为了定义肺上皮调节耐用粘膜T细胞免疫的机制。抵抗吸入的微生物被认为位于组织居民记忆（TRM）细胞中，但对此几乎一无所知鼻内疫苗诱导肺TRM。我们的初步数据表明，该疫苗会引起球虫剂保护内糖苷酶2（C-ENG2）特定的CD4+ T细胞以及支气管杆细胞和Ca ++钙调蛋白信号传导需要细胞以响应疫苗动员炎症和T细胞。我们还发现微量（M）细胞从支气管杆俱乐部细胞降下，并促进T细胞响应疫苗的启动。从这些初步数据中，我们假设支气管杆细胞和M细胞调节粘膜响应鼻内疫苗的细胞免疫。为了检验这一假设，我们创建了创新的工具：（i）转基因小鼠到纯上皮细胞亚群或其产物中，以进一步定义其在诱导免疫中的作用；（ii）C-ENG2特定的四聚体以跟踪和分析C57BL6小鼠中受保护的CD4+ T细胞和TRM；（iii）分离和培养人肺上皮细胞的方法将小鼠的结果转化为人类。我们建议三个旨在检验我们的假设的目的。在AIM 1中，我们将阐明炎症反应的早期阶段受支气管杆细胞和M细胞调节的鼻内疫苗；在AIM 2中，我们将确定肺上皮细胞受体 - dectin -1，duox1和duoxa1-以及下游PLCG2，可能会感觉到鼻内疫苗和通过Ca ++和钙调神经酶信号动员粘膜免疫；在AIM 3中，我们将定义通过研究肺TRM和肺上皮的调节作用，疫苗诱导的耐用粘膜免疫。总而言之，我们解决了针对球虫菌病的未满足疫苗接种的需求。我们的工作很重要它将定义有望疫苗在肺粘膜上建立T细胞免疫的机制。结果将确定对鼻内（包括亚基疫苗）的其他疫苗免疫原子有用的策略。工作将定义促进这种减毒疫苗或下一代亚基疫苗所需的免疫相关性违反这种高优先病原体。这项工作将使用最先进的尖端工具完成。我们的团队 Pi和Co-I的菜单将使我们通过人类肺上皮的工具和试剂将结果从小鼠转换为人类。