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.

不同种类的扁虱携带20多种病原体，包括A-C类和新出现/重新出现的病原体， 所有这些都能在人类中引起重大疾病，使目标对准扁虱而不是每个人 病原体有完善的干预策略.扁虱唾液分子调节宿主先天免疫和获得性免疫 防御，自然地促进了扁虱的饲养和病原体的传播。特别是，血液由 肩部硬蜱使宿主T淋巴细胞的反应极化，产生强烈的Th2细胞因子 配置文件，而获得性壁虱抗性(ATR)，一种与壁虱排斥反应和病原体有关的现象 传递障碍，与Th1细胞因子有关。这一建议是基于这样的假设： 在宿主中激发强大的ATR反应的疫苗接种策略也将提供对壁虱传播的保护 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 从扁虱转录本中识别候选疫苗，预计能激发强大的抗体和细胞介导性 人类的免疫力。将收集有关扁虱免疫相关因素的新信息 人类的唾液分子，以及对壁虱传播的病原体的潜在保护作用 在豚鼠(GP)模型中的传播。在目标1中，生物信息学、表位映射工具和微阵列， 用于鉴定、分离和鉴定肩峰唾液腺的关键抗原，并设计 基于表位的疫苗，刺激：1)壁虱致敏患者的PBMC中的Th1极化， 2)病原体传播的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 同样地，识别和分离与引起嗜碱性粒细胞脱颗粒的IgE抗体反应的扁虱分子 导致扁虱叮咬部位出现即刻类型的皮肤红斑/瘙痒反应。第三个目标包括 检测致敏人类在无病原体挑战下的ATR症状和免疫相关性 滴答滴答。此外，它结合了前两个目标的发现，并评估了一种由二价壁虱传播的疾病。 全科医生的传播疫苗策略。该项目的创新之处在于它应用了一种新的广谱 疫苗设计平台预计将显著加强“基因到疫苗”战略的翻译，以 人类。