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.

抽象的球孢子菌病是一种重新出现的感染，美国国立卫生研究院 (NIH) 已将其优先用于疫苗预防实验。减毒活孢子疫苗在鼻内给药后具有高度保护性，我们建议研究这种疫苗。确定肺上皮调节持久粘膜 T 细胞免疫的机制。吸入的微生物被认为存在于组织驻留记忆（TRM）细胞内，但人们对其如何产生知之甚少我们的初步数据表明，鼻内疫苗可诱导肺 TRM。内切葡聚糖酶 2 (C-Eng2) 特异性 CD4+ T 细胞以及细支气管俱乐部细胞和 Ca++ 钙调磷酸酶信号传导这些细胞需要动员炎症细胞和 T 细胞来响应疫苗。我们还发现 Microfold (M)。细胞源自细支气管棒状细胞，促进 T 细胞对疫苗的反应。从这些初步数据中，我们勇敢地相信细支气管俱乐部细胞和 M 细胞调节粘膜为了验证这一假设，我们创建了创新工具：（i）转基因小鼠消耗上皮细胞亚群或其产物，以进一步确定它们在诱导免疫中的作用； (ii) C-Eng2 特异性四聚体，用于追踪和分析 C57BL6 小鼠中的保护性 CD4+ T 细胞和 TRM；我们提出了分离和培养人肺上皮细胞的方法，以将小鼠的结果转化为人类。三个目标是检验我们的假设。在目标 1 中，我们将阐明炎症反应的早期阶段。目标2中，我们将鉴定由细支气管棒状细胞和M细胞调节的鼻内疫苗；受体 - dectin-1、DUOX1 和 DUOXA1 - 以及可能感知鼻内疫苗和下游 PLCG2 通过 Ca++ 和钙调神经磷酸酶发出信号来调动粘膜免疫；在目标 3 中，我们将定义其机制；通过研究肺 TRM 和肺上皮的调节作用，疫苗诱导持久的粘膜免疫。总之，我们解决了球孢子菌病疫苗接种的未满足需求，我们的工作意义重大。它将确定一种有前途的疫苗在肺粘膜上建立 T 细胞免疫的机制。将确定对鼻内给予的其他疫苗免疫原有用的策略，包括亚单位疫苗。将确定推进这种减毒疫苗或下一代亚单位疫苗所需的免疫相关性我们的团队将使用最先进的尖端工具来对抗这种高度优先的病原体。 PI 和 Co-I 将使我们能够使用针对人类肺上皮细胞的工具和试剂将结果从小鼠转化为人类。