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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.

摘要