Immuno-Proteomic Approach to Anti-Tick Vaccine Development

抗蜱疫苗开发的免疫蛋白质组学方法

基本信息

批准号：
8501256
负责人：
Thomas N Mather
金额：
$ 21.09万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501256
关键词：
Adjuvant Affect Affinity Antibodies Antigens Arthropod Vectors Back Basophils Binding Bioinformatics Bioterrorism Bite Black-legged Tick Blood Cavia Cellular Immunity Complementary DNA Computer software DNA Databases Dermal Development Disease Domestic Animals Emerging Communicable Diseases Epitope Mapping Epitopes Erythema Excision Felis catus Fingerprint Gene Expression Profile 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 Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spottings Symptoms T-Lymphocyte Tick-Borne Diseases Ticks Translations 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

Adjuvant Affect Affinity Antibodies Antigens Arthropod Vectors Back Basophils Binding Bioinformatics Bioterrorism Bite Black-legged Tick Blood Cavia Cellular Immunity Complementary DNA Computer software DNA Databases Dermal Development Disease Domestic Animals Emerging Communicable Diseases Epitope Mapping Epitopes Erythema Excision Felis catus Fingerprint Gene Expression Profile 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 Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spottings Symptoms T-Lymphocyte Tick-Borne Diseases Ticks Translations 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

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项目摘要

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.

各种壁虱具有20多种病原体，包括CAT A-C和新兴/重新出现的剂，所有人都能够在人类中引起严重的疾病，将目标定为tick而不是每个人病原体一种声音干预策略。滴答唾液分子调节宿主先天和适应性免疫防御，自然促进滴答喂养和病原体传播。特别是，血液通过 tick ixodes肩cap骨在宿主T淋巴细胞中的反应极化，导致Th2细胞因子剖面，而获得的tick抗性（ATR），这是一种与tick拒绝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引起宿主中强大的ATR响应的疫苗接种策略也将提供防止tick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预测可刺激稳健抗体和细胞介导的tick转录组中鉴定候选疫苗的候选物人类的免疫力。将收集有关免疫相关的新信息。人类中的唾液分子，以及针对tick传播病原体的潜在保护豚鼠（GP）模型的传播。在AIM 1，生物信息学，表位映射工具和微阵列中，用于识别，隔离和表征来自I. capularis唾液和设计的关键抗原刺激的基于表位的疫苗：1）PBMC的Th1极化，来自tick敏感的患者， 2）在病原体传播的GP模型中ATR。在AIM 2中，我们使用高吞吐量蛋白质组学工具来类似地识别和隔离tick分子，用IgE抗体反应引起basopophil脱粒的IgE抗体导致在tick咬位点立即型皮肤红斑/瘙痒反应。第三个目标包括测量敏感人类中ATR的症状和免疫相关性，无病原体挑战 tick。此外，它结合了前两个目的的发现，并评估了双重滴答疾病 GPS中的传输疫苗策略。该项目的创新在于其应用新颖的广泛范围预计疫苗设计平台将显着增强“疫苗基因为疫苗”策略的翻译人类。