Regulation of Skin Immunity by a Tick Bite

蜱虫叮咬对皮肤免疫的调节

• 批准号: 10514626
• 负责人: Joao Pedra
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514626
• 关键词: Affect; Anesthetics; Animal Model; Animals; Anti-Inflammatory Agents; Anticoagulants; Applications Grants; Arboviruses; Architecture; Area; Arthropods; Bacteria; Bar Codes; Biogenesis; Biological Assay; Biology; Biopsy; Bite; Black-legged Tick; Blood; Castor Bean Tick; Cattle; Cavia; Cell Communication; Cell Separation; Cells; Chromosome Mapping; Communities; Coupled; Dermal; Dermis; Disease; Emerging Technologies; Environment; Epidermis; Etiology; Europe; Fermentation; Flow Cytometry; Future; Gene Expression Profiling; Hemostatic Agents; Histology; Homeostasis; Human; Immune; Immune response; Immunity; Immunobiology; Immunology procedure; Inflammation; Intervention; Knowledge; Laboratories; Literature; Mammals; 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; 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

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：蜱传播细菌、病毒和寄生虫，引起人类和其他疾病