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.

摘要 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、无浆体病、米氏疏螺旋体病和壁虱传播的脑炎引起的病毒。动物 以虱子为食的食物可能会对反复喂食虱子产生抵抗力，而个别人类表现出不同的情况 对扁虱饲养的抵抗力水平。虽然在动物模型中已经了解了很多对蚤的反应， 最近的研究表明，扁虱会根据它们所捕食的宿主改变它们的唾液含量，并且 不同宿主对扁虱叮咬的免疫反应可能有很大不同。人类对扁虱叮咬的反应 由于难以获得一致的、可表征的样本，尚未进行系统研究。我们的 实验室参与了一项为期多年的研究，以检查将扁虱用作设备(异种诊断)的情况。 检测抗生素治疗后引起莱姆病的伯氏疏螺旋体的持久性 在病人身上。因此，我们收集了大量的血清、血浆、全血和皮肤。 扁虱叮咬部位周围的活检样本。在此，针对特定的RFA(PAR-18-860)来研究 对节肢动物摄食的免疫反应，我们建议研究人类的细胞和适应性免疫反应 并试图将每种蚊子叮咬的特定成分与对虱子进食的抵抗力联系起来。在目标1中，我们 将检查患者的皮肤活检样本，这些患者的扁虱喂养不良或良好，以确定细胞因子 使用RNAseq对咬伤做出反应的简档。我们还将确定其组织学特征。 扁虱叮咬部位周围有细胞渗入。利用空间转录学，我们将检查细胞 转录组，因为它与扁虱叮咬部位有关，并了解不同类型的细胞对 炎性环境。在目标2中，我们将确定获得性免疫反应对扁虱饲养的影响。 使用人工喂养膜，我们将测试喂养良好和喂养不良的患者的血清。 以及随着时间的推移和多次接触扁虱后进化的免疫反应的影响。在 这个项目的完成，我们将成功地建立人类免疫与 不成功的扁虱饲养，这将成为设计未来预防扁虱方法的基础 通过干扰扁虱饲养而传播的疾病。