Mechanisms of Vaccine Immunity against Coccidioidomycosis

球孢子菌病疫苗免疫机制

• 批准号: 10591641
• 负责人: BRUCE Steven KLEIN
• 金额: $ 48.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591641
• 关键词: Advanced Development; Antigen-Presenting Cells; Antigens; Attenuated; Attenuated Vaccines; Blastomyces dermatitidis; CD4 Positive T Lymphocytes; Calcineurin; Canis familiaris; Cell Culture Techniques; Cells; Cellular Immunity; Coccidioides; Coccidioidomycosis; Data; Dependence; Development; Elements; Epithelial; Epithelial Cells; Event; Fungal Vaccines; Generations; Genetic Polymorphism; Growth; Host resistance; Human; Immune; Immunity; Immunize; Infection; Infection Control; Inflammatory; Inflammatory Response; Inhalation; Innate Immune Response; Kinetics; Knowledge; Lung; Lymphoid Cell; Measures; Mechanics; Mediating; Medical; Memory; Modeling; Molecular; Mouse Strains; Mucosal Immunity; Mucous Membrane; Mus; Mycoses; Myelogenous; Myeloid Cells; PPP3R1 gene; Patients; Peptides; Phenotype; Preventive measure; Public Health; Regulation; Reporting; Reproduction spores; Resistance; Resistance development; Role; Shapes; Signal Pathway; Signal Transduction; Site; Structure of parenchyma of lung; Subunit Vaccines; Surface; System; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Translating; Translations; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Work; adaptive immune response; cytokine; dectin 1; draining lymph node; fungus; innovation; insight; memory CD4 T lymphocyte; mucosal vaccination; mucosal vaccine; novel; pathogen; pulmonary function; response; restraint; tool; transcriptome; transcriptomics; vaccine delivery

ABSTRACT We will exploit a live attenuated ∆cps1 (null) strain of Coccidiodes posadasii to vaccinate against coccidiodomycosis, and elucidate the mechanics by which the lung epithelium coordinates the induction of durable T cell immunity against infection. Host resistance against inhaled pathogens is thought to reside with lung tissue-resident memory (TRM) cells and mucosal immunity, but little is known about whether or how a fungal vaccine creates resident T cell immunity at the lung mucosa. Our preliminary data reveal that mucosal vaccination elicits protective, Coccidioides endoglucanase 2 (C-Eng2) specific CD4+ T cells and that the lung epithelium is required to mobilize myeloid and lymphoid cells in response to the vaccine. This network of stromal and hematopoetic cell responses to vaccination has not been studied and is the subject of this project. To define cellular and molecular mechanisms required to elicit protective immunity at the lung mucosa, we have created innovative tools: i) a novel protective antigen C-Eng2 and peptide:MHCII tetramers to track and enumerate protective CD4+ T cells in C57BL6 in mice; ii) transgenic mice in which epithelial cells and their products are able to be conditionally deleted to dissect their role in generation of immunity; and (iii) a novel system of isolating and culturing human lung epithelium to translate results from mice to humans. We hypothesize that the mucosal delivery of ∆cps1 vaccine spores promotes devel- opment of protective TRM cells and that the lung epithelium coordinates durable protective immunity. We aim to: 1. Probe the intial stages of vaccine recognition and response by innate immune cells in lung. We will test the hypothesis that lung epithelium and their products regulate mobilization of innate immune cells that recognize and restrain growth of ∆cps1 vaccine spores, and also captures them to present their peptides to naïve T cells in the draining lymph nodes. 2. Elucidate intracellular signaling pathway during lung epithelial cell regulation of innate response to ∆cps1 vaccine. We will test the hypothesis that Ca++ and calcineurin dependent signaling events within the lung epithelium contribute to the dectin-1 dependency of host inflammatory responses to Coccidiodes spp. and vaccine in both mice and humans. 3. Define mechanisms of durable T cell immunity elicited by vaccination at the lung mucosa. We will test the hypothesis that lung epithelium shapes the phenotypic, functional and transcriptomic features of protective C-Eng2-specific CD4+ T cells following intransal administration ∆cps1 vaccine spores . Our work will exploit a highly effective vaccine against coccidioidomycosis to elucidate the mechanisms of lung immunity following mucosal administration. Little is known about the mechanisms of vaccine-induced protective immunity at the lung mucosa, and how the lung epithelium regulates the early recognition and restraint of vaccine spores and generation of protective T cells. Vaccination against coccidioidomycosis, an important public health problem, is a major unmet medical need. We anticipate that new insight into the mechanistic underpinnings of vaccine induced mucosal resistance, and the immune correlates of vaccine resistance will advance the development of preventive measures against coccidioidomycosis.

抽象的 我们将探索coccidiodes posadasii的活体减弱ΔCPS1（NULL）菌株，以疫苗接种球cosiodiodycomisois，并 阐明肺上皮坐在耐受性T细胞免疫诱导感染的力学。 人们认为对遗传病原体的抗药性与肺组织居民记忆（TRM）细胞和粘膜相处。 免疫力，但对真菌疫苗是在肺粘膜上产生居民T细胞免疫的知之甚少。 我们的初步数据表明，粘膜疫苗接种会引起球虫葡萄糖酶2（C-ENG2）特定 CD4+ T细胞和肺上皮需要响应疫苗动员髓样细胞和淋巴样细胞。 这种对疫苗接种的基质和造血细胞反应网络尚未研究，并且是该项目的主题。 为了定义在肺粘膜下引起受保护的免疫所需的细胞和分子机制，我们创造了 创新工具：i）一种新型受保护的抗原C-ENG2和胡椒：MHCII四聚体，可追踪和枚举受保护的CD4+ 小鼠C57BL6中的T细胞； ii）上皮细胞及其产物能够有条件删除的转基因小鼠 剖析他们在产生免疫力中的作用； （iii）一种新型的隔离和培养人肺上皮的系统 将小鼠的结果转换为人类。我们假设ΔCPS1疫苗孢子的粘膜递送促进了Devel- 选择受保护的TRM细胞的选择，肺上皮坐标可持久保护性免疫。我们的目标是： 1。探测肺部先天免疫细胞的疫苗识别和反应的直觉阶段。我们将检验假设 肺上皮及其产物调节了识别和抑制生长的先天免疫小球的动员 ∆CPS1疫苗孢子的孢子，还捕获它们以将其宠物呈现给排水淋巴结中的幼稚T细胞。 2。阐明对ΔCPS1疫苗的先天反应的肺上皮细胞调节期间的细胞内信号通路。 我们将检验以下假设，即肺上皮内的Ca ++和钙调神经酶依赖性信号传导事件有助于 对宿主对coccidiodes spp宿主炎症反应的依赖性。和小鼠和人类的疫苗。 3。定义肺粘膜疫苗接种引起的耐用T细胞免疫的机制。我们将检验假设 肺上皮塑造了受保护的C-ENG2特异性CD4+的表型，功能和转录特征 植物给药后的T细胞ΔCPS1疫苗孢子。 我们的工作将利用高效的疫苗针对球虫菌病，以阐明肺部免疫霍斯托的机制 粘膜给药后。关于疫苗诱导的保护性免疫的机制知之甚少 肺粘膜，以及肺上皮如何调节疫苗孢子的早期识别和约束和产生 保护性T细胞。针对球虫菌病的疫苗接种是一个重要的公共卫生问题，是一个主要的未经医疗 需要。我们预计，对疫苗诱导粘膜抗性的机械基础的新见解，以及 疫苗耐药性的免疫相关性将推动针对球虫病的预防措施的发展。