Regulation of Skin Immunity by a Tick Bite

蜱虫叮咬对皮肤免疫的调节

基本信息

批准号：
10337568
负责人：
Joao Pedra
金额：
$ 23.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337568
关键词：
Affect Anesthetics Animal Model Animals Anti-Inflammatory Agents Anticoagulants Applications Grants Arboviruses Architecture Area Arthropods Bacteria Bar Codes Biogenesis Biology Biopsy Bite Black-legged Tick Blood Castor Bean Tick Cattle Cavia Cell Separation Cells Communities Coupled Dermal Dermis Disease Environment Epidermis Etiology Europe Flow Cytometry Future Gene Expression Profiling Genes Hemostatic Agents Histology Homeostasis Human Immune Immune response Immunity Immunobiology Immunology procedure Inflammation Intervention Knowledge Laboratories Lead Literature Mammals Maps Measures Mediating Molecular Molecular Analysis Mus N-ethylmaleimide-sensitive protein Organoids Parasites Population Property Proteins RNA RNA Interference Reagent Receptor Gene Regulation Research Research Personnel Resistance Resources Role Saliva Salivary Salivary Glands Salivary Proteins Seminal Site Skin System T-Lymphocyte Technology Therapeutic Thinking Tick-Borne Diseases Ticks Travel United States Virus Work acquired immunity arthropod-borne base extracellular vesicles fascinate feeding follow-up foot functional plasticity immunoregulation insight interspecies communication keratinocyte microbial nanovesicle neglect new technology pathogen receptor single-cell RNA sequencing tick bite tick feeding tick saliva tick transmission tool transcriptomics transmission process vector vesicular release wound healing γδ T cells

项目摘要

Summary/Abstract: Ticks transmit bacteria, viruses and parasites that cause disease in humans and other animals. This phenomenon is partly due to the secretion of redundant and pluripotent salivary proteins that disrupt host homeostasis and alter inflammation upon blood-feeding. Recently, extracellular vesicles, a heterogenous population of nanovesicles that mediate interspecies communication, were shown to facilitate pathogen transmission to mammals. We developed a tick salivary organoid system that mimics extracellular vesicle release. We also manipulated the biogenesis of tick extracellular vesicles by silencing the expression of N-ethylmaleimide-sensitive factor attachment receptor (SNARE) genes through RNA interference. Finally, we provided causality to our findings by showing that tick extracellular vesicles affect resident dendritic epidermal T cells (DETCs) in the skin. How immune cells are targeted by tick nanovesicles in the skin remains unsettled. Whether tick extracellular vesicles have functional plasticity during interspecies relationships remains elusive. In this R21 application, we will explore the central hypothesis that tick extracellular vesicles provide an advantageous skin immune environment for Ixodes scapularis feeding via the DETC-keratinocyte axis. DETCs interact with keratinocytes, which comprise approximately 95% of the skin epidermal layer. In Aim #1 of this proposal, we will determine whether the effect of I. scapularis extracellular vesicles on DETCs is direct or indirect. We will use single cell RNA sequencing coupled with animal models devoid of DETCs to evaluate the directionality of the skin immune response during a tick bite. In Aim #2 of this grant proposal, we will ascertain the architecture of the skin when the biogenesis of tick extracellular vesicles is disrupted. We will measure the immune response of DETCs through skin biopsies via flow cytometry coupled with cell sorting, microbial stimulation and spatial transcriptomics. Spatial transcriptomics combines traditional histology information with single cell gene expression analysis and positional barcoding. Thus, we will construct an architectural map of genes associated with DETCs and keratinocytes during a tick bite. Collectively, this R21 project will underscore the importance of ticks as arthropods of

摘要/摘要：tick传输引起人类和其他引起疾病的细菌，病毒和寄生虫动物。这种现象部分是由于冗余和多能唾液蛋白的分泌干扰宿主的稳态并在喂食时会改变炎症。最近，细胞外囊泡，一个介导种间通信的纳米植物的异质种群被证明有助于病原体向哺乳动物传播。我们开发了一个模仿细胞外的滴答唾液器官系统囊泡释放。我们还通过沉默表达来操纵壁虱细胞外囊泡的生物发生通过RNA干扰，N-乙基马来酰亚胺敏感因子附着受体（SNARE）基因。最后，我们通过表明壁虱外囊泡影响居民树突，为我们的发现提供了因果关系皮肤表皮T细胞（DETC）。免疫细胞是如何由皮肤中的壁虱纳米群靶向的未安排。在种间关系期间，tick细胞外囊泡是否具有功能可塑性仍然难以捉摸。在此R21应用程序中，我们将探讨滴答细胞外囊泡的中心假设通过destc-keratinopyte提供有利的皮肤免疫环境，用于肩cap骨喂养轴。 DETC与角质形成细胞相互作用，其中约占皮肤表皮层的95％。目标该提案的＃1，我们将确定肩cap膜外囊泡对开发的影响是否是直接或间接。我们将使用单个细胞RNA测序，结合没有开发的动物模型评估tick咬时皮肤免疫反应的方向性。在本赠款提案的AIM＃2中，我们当壁虱外囊泡的生物发生破坏时，将确定皮肤的结构。我们将通过流式细胞术和细胞分选，测量通过皮肤活检的发射动作的免疫反应，微生物刺激和空间转录组学。空间转录组学结合了传统的组织学带有单细胞基因表达分析和位置条形码的信息。因此，我们将构建一个 tick咬时，基因的建筑图和角质形成细胞相关。总的来说，这是R21 项目将强调tick作为节肢动物的重要性