Understanding Human Immunological Responses to Ixodes Tick Bites

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、无形体病、宫本疏螺旋体病和蜱传脑炎引起的病毒。动物 被蜱虫取食可能会对反复的蜱虫取食产生抵抗力， 对蜱虫喂食的抵抗力虽然已经了解了很多关于模型动物对蜱虫的反应， 最近的研究表明，蜱根据它们所取食的宿主改变它们的唾液含量， 对蜱叮咬的免疫反应在宿主之间可以显著不同。人类对蜱虫叮咬的反应 由于难以获得一致的、可表征的样品，尚未进行系统研究。我们 实验室参与了一项为期多年的研究，以检查使用蜱作为一种设备（异种诊断）， 检测抗生素治疗后莱姆病病原体伯氏疏螺旋体的持续存在 在病人身上。因此，我们有大量的、特征良好的血清、血浆、全血和皮肤样本 从蜱虫叮咬处采集的活检样本在这里，为了响应特定RFA（PAR-18-860）来研究 免疫反应节肢动物喂养，我们建议研究人类细胞和适应性免疫反应 并试图将每种物质的特定成分与对蜱虫取食的抵抗力联系起来。目标1： 将检查蜱虫进食不良或良好患者的皮肤活检样本，以确定细胞因子 使用RNAseq对咬的响应的概况。我们还将确定的组织学特征， 蜱虫叮咬部位周围有细胞浸润使用空间转录组学，我们将研究细胞 转录组，因为它涉及到蜱叮咬的网站，并了解不同类型的细胞的贡献， 炎症环境在目标2中，我们将确定适应性免疫应答对蜱虫摄食的影响。 使用人工喂养膜，我们将测试来自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演变的免疫反应的影响。在 完成这个项目后，我们将建立成功的人类免疫相关性， 不成功的蜱虫喂养，这将成为设计未来预防蜱虫方法的基础 通过干扰蜱虫进食传播疾病。

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.