Regulation of vaccine-induced anti-fungal Th17 cells

疫苗诱导的抗真菌 Th17 细胞的调节

• 批准号: 9381740
• 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
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381740
• 关键词: Achievement; Address; Adjuvant; Adjuvanticity; Adoptive Transfer; Affect; Alpha Cell; 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; Helper-Inducer T-Lymphocyte; 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; Microbe; Modification; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Mycoses; Particulate; Pathogenicity; Patients; Phagocytes; Polysaccharides; Proteins; Public Health; Recruitment Activity; Regulation; Reporter; Research; Resistance; Resolution; Spectrophotometry; Structure; Subunit Vaccines; System; T cell response; T-Lymphocyte; Testing; Th1 Cells; Trehalose; United States; Vaccination; Vaccines; Vertebral column; Work; aluminum sulfate; base; clinically relevant; combat; cytokine; design; fungus; glycosylation; high risk; in vivo; insight; killings; man; mannoproteins; microbial; mouse dectin-2; novel; novel strategies; novel vaccines; pathogen; polarized cell; protective efficacy; receptor; response; screening; uptake; vaccine development

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.

项目总结/摘要 预防传染病的疫苗被誉为20世纪以来公共卫生领域最伟大的成就。 上个世纪。这种竞争性的更新将研究一种新的佐剂，增强细胞免疫反应 需要更好的疫苗。缺乏合适的佐剂是开发安全和有效的佐剂的一个主要障碍。 针对真菌病原体感染的有效疫苗，其代表医学中未满足的需求， 公共卫生尽管严重真菌感染的发病率不断上升，但商业上还没有针对真菌的疫苗。 available.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有限。细胞免疫对于解决 真菌感染实验模型中疫苗诱导的抗真菌抗性需要Th 17和Th 1 细胞产生IL-17和IFN-γ，并部分通过募集和激活吞噬细胞来介导保护作用， 增强对真菌的杀灭。在上一个资助周期中，我们发现真菌识别的C型凝集素 Dectin-2是分化保护性Th 17和Th 1细胞对抗二型性免疫缺陷所必需的。 真菌通过生化纯化和质谱分析，鉴定了一种新的天然产物 Dectin-2的真菌配体，糖蛋白Blastomerase Eng 3（Bl-Eng 3）。 在本申请中，我们提出表征和功能测试Bl-Eng 3作为疫苗接种的佐剂 对抗真菌我们假设Bl-Eng 3激活树突状细胞，驱动抗原的分化， （Ag）特异性Th 17和Th 1细胞，从而促进针对真菌的保护性细胞免疫 感染我们还证实，蛋白质骨架和聚糖修饰占配体活性 B1-Eng 3单独或与其它β配体一起将是疫苗的有效佐剂 对抗真菌我们提供了强有力的初步数据来支持我们的假设。使用Dectin-2报告细胞， 我们已经建立了一个体外筛选系统，以剖析蛋白质骨架及其 糖基化对Dectin-2配体活性的影响和体内过继转移系统，以描述糖基化对Dectin-2配体活性的影响。 配体佐剂对幼稚抗原特异性CD 4 + T细胞分化为保护性Th 17和Th 1细胞的作用。 我们的方法提供了一个强大的互补策略，将确定糖蛋白的配体部分， 目的1，评估抗原提呈细胞（APCs）和抗原特异性T细胞成熟和致敏的能力 在目标2中，并确定受体与其他CLR协作以及实验模型中的保护功效 肺部和全身真菌感染的发病率。我们的工作将为促进 APC的成熟和保护性Th 17和Th 1细胞的分化。这些知识将提供基础 用于开发和设计针对真菌和其他病原微生物的新疫苗策略， 细胞免疫来防御宿主