Immuno-Proteomic Approach to Anti-Tick Vaccine Development

抗蜱疫苗开发的免疫蛋白质组学方法

• 批准号: 7696402
• 负责人: Thomas N Mather
• 金额: $ 26.78万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696402
• 关键词: Adjuvant; Affect; Affinity; Antibodies; Antigens; Arthropod Vectors; Arts; Back; Basophils; Binding; Bioinformatics; Bioterrorism; Bite; Black-legged Tick; Blood; Cavia; Cellular Immunity; Computer software; DNA; Databases; Dermal; Development; Disease; Domestic Animals; Emerging Communicable Diseases; Epitope Mapping; Epitopes; Erythema; Excision; Felis catus; Fingerprint; Genes; Genetic; HLA Antigens; Human; IgE; Immune; Immune Sera; Immune response; Immunity; Immunization; Immunology; Immunotherapeutic agent; Impairment; In Situ; Individual; Infection; Informatics; Intervention; Investigation; Liquid Chromatography; Maps; Mass Spectrum Analysis; Measures; Methods; Mining; Modeling; Patients; Peptides; Proteins; Proteomics; Public Health; Reaction; Recombinant Proteins; Research; Resistance; Role; Route; Saliva; Salivary; Salivary Glands; Salivary Proteins; Sampling; Site; Solutions; Spottings; Symptoms; T-Lymphocyte; Tick-Borne Diseases; Ticks; Translations; Triad Acrylic Resin; Trypsin; Two-Dimensional Gel Electrophoresis; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Vector-transmitted infectious disease; base; biodefense; cytokine; design; disease transmission; feeding; fighting; human subject; immunogenic; immunogenicity; improved; in vitro testing; innovation; novel; pathogen; potency testing; prevent; response; sound; tool; transmission process; two-dimensional; vaccination strategy; vaccine candidate; vaccine development

Various species of ticks carry more than 20 pathogens, including Cat A-C and emerging/re-emerging agents, all capable of causing significant disease in humans, making targeting the tick instead of each individual pathogen a sound intervention strategy. Tick salivary molecules modulate host innate and adaptive immune defenses, naturally facilitating both tick feeding and pathogen transmission. In particular, blood feeding by the tick Ixodes scapularis polarizes responses in host T lymphocytes resulting in a strongly Th2 cytokine profile, while acquired tick resistance (ATR), a phenomenon associated with tick rejection and pathogen transmission impairment, is associated with Th1 cytokines. This proposal is based on the hypothesis that a vaccination strategy evoking a robust ATR response in hosts also will provide protection against tick-borne pathogen transmission. Using state-of-the-art informatics and proteomics methods, our primary objective is to identify vaccine candidates from tick transcriptomes predicted to stimulate robust antibody- and cellmediated immunity in humans. New information will be gathered regarding correlates of immunity to tick salivary molecules in humans, and potential correlates of protection against tick-borne pathogen transmission in a Guinea pig (GP) model. In aim 1, bioinformatics, epitope mapping tools, and microarrays, are used to identify, isolate and characterize critical antigens from the I. scapularis salivome and design epitope-based vaccines that stimulate: 1) Th1 polarization in PBMCs derived from tick-sensitized patients, and 2) ATR in a GP model of pathogen transmission. In aim 2, we use high throughput proteomic tools to similarly identify and isolate tick molecules reactive with IgE antibodies that elicit basophil degranulation resulting in an immediate-type dermal erythema/itch reaction at the tick bite site. The third aim includes measuring symptoms and immune correlates of ATR in sensitized humans challenged with pathogen-free ticks. Additionally, it combines findings from the first two aims and evaluates a bi-valent tick-borne disease transmission vaccine strategy in GPs. This project's innovation is in its application of a novel broad spectrum platform for vaccine design expected to significantly enhance translation of a "gene to vaccine" strategy to humans.

各种蜱虫携带 20 多种病原体，包括 Cat A-C 和新出现/重新出现的病原体， 所有这些都能够在人类中引起重大疾病，从而使目标对准蜱而不是每个个体 病原菌健全的干预策略。蜱唾液分子调节宿主先天和适应性免疫 防御，自然促进蜱虫进食和病原体传播。特别是，通过血液喂养 肩胛硬蜱使宿主 T 淋巴细胞的反应极化，产生强烈的 Th2 细胞因子 概况，而获得性蜱抗性（ATR）是一种与蜱排斥和病原体相关的现象 传输障碍与 Th1 细胞因子有关。该提议基于以下假设： 疫苗接种策略在宿主体内引起强烈的 ATR 反应也将提供针对蜱传病毒的保护 病原体传播。使用最先进的信息学和蛋白质组学方法，我们的主要目标是 从蜱转录组中鉴定候选疫苗，预测可刺激强大的抗体和细胞介导 人类的免疫力。将收集有关蜱虫免疫力相关性的新信息 人类唾液分子以及预防蜱传病原体的潜在相关性 豚鼠（GP）模型中的传播。在目标 1 中，生物信息学、表位作图工具和微阵列， 用于鉴定、分离和表征来自肩胛 I. scapularis 唾液组的关键抗原并设计 基于表位的疫苗可刺激：1) 来自蜱敏感患者的 PBMC 中的 Th1 极化， 2) 病原体传播 GP 模型中的 ATR。在目标 2 中，我们使用高通量蛋白质组学工具 类似地识别和分离与 IgE 抗体反应的蜱分子，引起嗜碱性粒细胞脱颗粒 导致蜱虫叮咬部位立即出现皮肤红斑/瘙痒反应。第三个目标包括 测量接受无病原体攻击的致敏人群中 ATR 的症状和免疫相关性 滴答声。此外，它结合了前两个目标的发现，并评估了二价蜱传疾病 全科医生的传播疫苗策略。该项目的创新在于其应用了一种新颖的广谱 疫苗设计平台有望显着增强“基因到疫苗”战略的转化 人类。