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: 8114214
• 负责人: Thomas N Mather
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8114214
• 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; 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.

不同种类的蜱携带20多种病原体，包括Cat A-C和新出现/再出现的病原体， 所有这些都能在人类中引起重大疾病，使目标对准蜱虫，而不是每个个体， 病原体的合理干预策略。蜱唾液分子调节宿主先天性和适应性免疫 防御，自然促进蜱虫进食和病原体传播。特别是， 肩突硬蜱使宿主T淋巴细胞的反应极化，导致强烈的Th 2细胞因子 而获得性蜱抗性（ATR），一种与蜱排斥和病原体相关的现象， 传递障碍与Th 1细胞因子有关。这一建议是基于这样的假设，即 在宿主中引起强烈ATR反应的疫苗接种策略也将提供针对蜱传 病原体传播利用最先进的信息学和蛋白质组学方法，我们的主要目标是 从蜱虫转录组中识别候选疫苗，预计可刺激强有力的抗体和细胞介导的 人类的免疫力。新的信息将收集有关免疫力的相关蜱 人类唾液中的分子，以及对抗蜱传病原体的潜在相关性 在豚鼠（GP）模型中的传播。在aim 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I.肩胛肌涎管及设计 基于表位的疫苗，其刺激：1）来自蜱致敏患者的PBMC中的Th 1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， 类似地鉴定和分离与IgE抗体反应蜱分子，其引起嗜碱性粒细胞脱粒 导致蜱叮咬部位的即刻型皮肤红斑/瘙痒反应。第三个目标包括 测量无病原体激发的致敏人类中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，并评估了一种双价蜱传疾病 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颖的广谱 一个疫苗设计平台有望显著增强“基因到疫苗”战略的转化， 人类