Understanding Human Immunological Responses to Ixodes Tick Bites

了解人类对硬蜱叮咬的免疫反应

• 批准号: 9807836
• 负责人: Linden T Hu
• 金额: $ 20.63万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-13 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807836
• 关键词: Anaplasmosis; Animal Model; Animals; Antibiotic Therapy; Antibodies; Antigens; Arthropods; Artificial Feeding; Artificial Membranes; Babesiosis; Bacteria; Behavior; Belief; Biology; Biopsy; Biopsy Specimen; Bite; Black-legged Tick; Blood specimen; Borrelia burgdorferi; Borrelia miyamotoi; Cavia; Cells; Cellular Immunity; Characteristics; Collection; Data; Deer Tick; Development; Devices; Disease; Erythema; Evolution; Exposure to; Future; Goals; Histologic; Histology; Human; Immune; Immune response; Immune system; Immunity; Immunize; Immunology; Individual; Infection; Inflammatory; Inflammatory Response; Ixodes; Laboratories; Leucocytic infiltrate; Lyme Disease; Measures; Membrane; Mus; Organism; Patients; Peromyscus; Plasma; Play; Positioning Attribute; Predisposition; Pruritus; Reaction; Recording of previous events; Residual state; Resistance; Resistance development; Risk; Role; Salivary; Salivary Proteins; Sampling; Serum; Site; Skin; Specimen; Techniques; Testing; Tick-Borne Diseases; Tick-Borne Encephalitis; Tick-Borne Infections; Ticks; Time; Virus; Whole Blood; Xenodiagnosis; adaptive immune response; adaptive immunity; base; cell type; cytokine; design; disease transmission; experience; feeding; granulocyte; human disease; immunoreaction; inflammatory milieu; innovative technologies; pathogen; prevent; resistance mechanism; response; success; transcriptome; transcriptome sequencing; transcriptomics; transmission process; vector; vector tick

ABSTRACT Ixodes ticks are vectors of many important human diseases including but not limited to Lyme disease, babesiosis, anaplasmosis, Borrelia miyamotoi disease, and tick-borne encephalitis causing viruses. Animals fed on by ticks may develop resistance to repeated tick feedings and individual humans have shown differing levels of resistance to tick feeding. While much has been learned about responses to ticks in model animals, recent studies have shown that ticks alter their salivary content based on the host they are feeding on and that immunological responses to tick bites can vary significantly between hosts. Human responses to tick bites have not been studied systematically due to the difficulty in obtaining consistent, characterizable samples. Our laboratories are involved in a multi-year study to examine the use of ticks as a device (xenodiagnosis) for detecting the persistence of the Lyme disease causing organism, Borrelia burgdorferi, after antibiotic treatment in patients. As a result, we have a large, well characterized collection of serum, plasma, whole blood and skin biopsy samples from around tick bite sites. Here, in response to a specific RFA (PAR-18-860) to study the Immune Response to Arthropod feeding, we propose to study human cellular and adaptive immune responses to tick bites and attempt to correlate specific components of each with resistance to tick feeding. In Aim 1, we will examine skin biopsy samples from patients where ticks fed either poorly or well to determine the cytokine profile in response to the bite using RNAseq. We will also determine the histological characteristics of the cellular infiltrate around the tick bite site. Using spatial transcriptomics, we will examine the cellular transcriptome as it relates to the tick bite site and understand the contribution of different cell types to the inflammatory milieu. In Aim 2, we will determine the impact of the adaptive immune response on tick feeding. Using artificial feeding membranes, we will test serum from patients who experienced good and poor feeding as well as the effects of the evolving immune response over time and after multiple exposures to ticks. At the completion of this project, we will have established the human immune correlates of successful and unsuccessful tick feeding which will form the building blocks for designing future approaches to preventing tick borne diseases through interfering with tick feeding.

抽象的 硬蜱是许多重要人类疾病的媒介，包括但不限于莱姆病、 巴贝斯虫病、无形体病、宫本疏螺旋体病和蜱传脑炎病毒。动物 以蜱虫为食的动物可能会对重复的蜱虫喂食产生抵抗力，并且人类个体表现出不同的抵抗力 对蜱虫进食的抵抗力水平。虽然我们已经了解了模型动物对蜱虫的反应， 最近的研究表明，蜱虫会根据其所吃的宿主来改变其唾液含量，并且 不同宿主对蜱虫叮咬的免疫反应可能存在显着差异。人类对蜱虫叮咬的反应 由于难以获得一致的、可表征的样本，尚未对其进行系统研究。我们的 实验室参与了一项多年研究，以检查蜱虫作为一种设备（异种诊断）的用途 检测抗生素治疗后莱姆病致病菌伯氏疏螺旋体的持续存在 在患者中。因此，我们拥有大量、特征明确的血清、血浆、全血和皮肤样本 蜱虫叮咬部位周围的活检样本。在此，响应特定的 RFA (PAR-18-860) 来研究 对节肢动物进食的免疫反应，我们建议研究人类细胞和适应性免疫反应 蜱虫叮咬，并尝试将每种成分的特定成分与对蜱虫进食的抵抗力联系起来。在目标 1 中，我们 将检查蜱虫喂养不良或良好的患者的皮肤活检样本，以确定细胞因子 使用 RNAseq 分析对咬伤的响应。我们还将确定组织学特征 蜱虫叮咬部位周围有细胞浸润。使用空间转录组学，我们将检查细胞 转录组与蜱虫叮咬部位相关，并了解不同细胞类型对蜱虫叮咬部位的贡献 炎症环境。在目标 2 中，我们将确定适应性免疫反应对蜱进食的影响。 使用人工喂养膜，我们将测试经历良好和不良喂养的患者的血清 以及随着时间的推移和多次接触蜱虫后不断变化的免疫反应的影响。在 该项目完成后，我们将建立成功和成功的人类免疫相关性 不成功的蜱虫喂养将为设计未来预防蜱虫的方法奠定基础 通过干扰蜱虫进食传播疾病。