Regulation of vaccine-induced anti-fungal Th17 cells

疫苗诱导的抗真菌 Th17 细胞的调节

基本信息

批准号：
9976397
负责人：
Marcel Wuethrich
金额：
$ 56.05万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-03 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976397
关键词：
Achievement Address Adjuvant Adjuvanticity Adoptive Transfer Affect Animals Antibodies Antibody Formation Antifungal Agents Antigen-Presenting Cells Antigens Aspergillus fumigatus Biochemical Blastomyces C Type Lectin Receptors CD4 Positive T Lymphocytes Candida albicans Cause of Death Cell Differentiation process Cells Cellular Immunity Clinical Collaborations Common Core Communicable Diseases Data Dendritic Cells Development Differentiation Antigens Effectiveness Experimental Models Formulation Foundations Funding Fungal Vaccines Glucans Glycoproteins Goals Host Defense Human Immune response Immunity In Vitro Infection Inflammatory Interferon Type II Interleukin-17 Knowledge Ligands Ligation Link Lung Mannans Mannose Mannosyltransferases Mass Fragmentography Measures Mediating Medical Medicine Modification Monoclonal Antibodies Mus Mycobacterium tuberculosis Mycoses Particulate Patients Phagocytes Polysaccharides Proteins Public Health Regulation Reporter Research Resistance Resolution Spectrophotometry Structure Subunit Vaccines System T cell response Testing Th1 Cells Trehalose United States Vaccination Vaccines Vertebral column Work aluminum sulfate antigen-specific T cells base clinically relevant combat cytokine design fungus glycosylation high risk in vivo insight man mannoproteins mouse dectin-2 novel novel strategies novel vaccines pathogenic fungus pathogenic microbe polarized cell protective efficacy receptor recruit response screening uptake vaccine development

项目摘要

Project Summary/Abstract Vaccines against infectious diseases have been hailed as the greatest achievement in public health over the last century. This competing renewal will investigate a novel adjuvant that elicits cellular immune responses needed for better vaccines. The lack of an appropriate adjuvant is one major barrier to developing a safe and effective vaccine against infections with fungal pathogens, which represents an unmet need in medicine and public health. Despite the rising rates of severe fungal infections, no vaccines against fungi are commercially available. While current vaccines against infectious diseases preferentially induce production of antibodies, their contribution to host defense against fungi is limited. Cellular immunity is essential for the resolution of fungal infections. Vaccine-induced resistance against fungi in experimental models requires Th17 and Th1 cells that produce IL-17 and IFN-γ and mediate protection in part by recruiting and activating phagocytes to augment killing of fungi. In the last funding cycle, we discovered that fungal recognition by the C-type lectin receptor (CLR) Dectin-2 is required for the differentiation of protective Th17 and Th1 cells against dimorphic fungi. Through biochemical purification and mass spectrophotometry analysis, we identified a novel bona-fide fungal ligand for Dectin-2, the glycoprotein Blastomyces Eng3 (Bl-Eng3). In this application, we propose to characterize and functionally test Bl-Eng3 as an adjuvant for vaccination against fungi. We hypothesize that Bl-Eng3 activates dendritic cells, drives differentiation of antigen (Ag)-specific Th17 and Th1 cells, and thereby promotes protective cellular immunity against fungal infection. We also posit that the protein backbone and glycan modifications account for ligand activity and that Bl-Eng3 will be an effective adjuvant alone or together with other CLR ligands for vaccines against fungi. We provide strong preliminary data to support our hypotheses. Using Dectin-2 reporter cells, we have established an in vitro screening system to dissect the contributions of the protein backbone and its glycosylation to Dectin-2 ligand activity and an in vivo adoptive transfer system to delineate the effects of the ligand adjuvant on the differentiation of naïve antigen-specific CD4+ T-cells into protective Th17 and Th1 cells. Our approach offers a powerful complimentary strategy that will identify the ligand moiety of the glycoprotein in aim 1, assess adjuvancy for the maturation and priming of Ag-presenting cells (APCs) and Ag-specific T cells in aim 2, and determine receptor collaboration with other CLRs and protective efficacy in experimental models of pulmonary and systemic fungal infections in aim 3. Our work will provide new insight needed to promote the maturation of APCs and differentiation of protective Th17 and Th1 cells. This knowledge will provide the basis for developing and designing new vaccine strategies against fungi, and other pathogenic microbes that require cellular immunity for host defense.

项目概要/摘要传染病疫苗被誉为近百年来公共卫生领域最伟大的成就这一竞争性的更新将研究一种引发细胞免疫反应的新型佐剂。缺乏合适的佐剂是开发安全且有效的疫苗的一个主要障碍。针对真菌病原体感染的有效疫苗，这代表了医学和医学方面未满足的需求尽管严重真菌感染的发病率不断上升，但还没有针对真菌的疫苗投入商业化。虽然目前针对传染病的疫苗优先诱导抗体的产生，它们对宿主防御真菌的贡献是有限的。实验模型中疫苗诱导的真菌抵抗需要 Th17 和 Th1。产生 IL-17 和 IFN-γ 的细胞，部分通过招募和激活吞噬细胞来介导保护在上一个资助周期中，我们发现 C 型凝集素可以识别真菌。受体 (CLR) Dectin-2 是针对二态性的保护性 Th17 和 Th1 细胞分化所必需的通过生化纯化和质谱分析，我们鉴定出了一种新型的真正的真菌。 Dectin-2 的真菌配体，糖蛋白芽生菌 Eng3 (Bl-Eng3)。在此应用中，我们建议对 Bl-Eng3 作为疫苗接种佐剂进行表征和功能测试我们认为 Bl-Eng3 可以激活树突状细胞，驱动抗原分化。 (Ag) 特异性 Th17 和 Th1 细胞，并促进针对真菌的保护性细胞免疫我们还假设蛋白质骨架和聚糖修饰解释了配体活性。并且 Bl-Eng3 将单独或与其他 CLR 配体一起成为疫苗的有效佐剂我们使用 Dectin-2 报告细胞提供了强有力的初步数据来支持我们的假设。我们建立了一个体外筛选系统来剖析蛋白质骨架的贡献及其 Dectin-2配体活性的糖基化和体内过继转移系统来描述Dectin-2配体活性的影响配体佐剂对幼稚抗原特异性 CD4+ T 细胞分化为保护性 Th17 和 Th1 细胞的影响。我们的方法提供了一个强大的补充策略，可以识别糖蛋白的配体部分目标 1，评估 Ag 呈递细胞 (APC) 和 Ag 特异性 T 细胞的成熟和启动的佐剂作用目标 2，确定受体与其他 CLR 的协作以及实验模型中的保护功效目标 3 中的肺部和全身真菌感染。我们的工作将为促进 APC 的成熟以及保护性 Th17 和 Th1 细胞的分化将提供基础。用于开发和设计针对真菌和其他需要的病原微生物的新疫苗策略宿主防御的细胞免疫。