Tick Immune Signaling, Microbiota, and Acquisition of Borrelia burgdorferi and Anaplasma phagocytophilum

蜱免疫信号传导、微生物群以及伯氏疏螺旋体和嗜吞噬细胞无形体的获得

• 批准号: 10222514
• 负责人: Erol Fikrig
• 金额: $ 153.75万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222514
• 关键词: Address; Anaplasma phagocytophilum; Anaplasmosis; Area; Biological; Biological Assay; Black-legged Tick; Blood; Borrelia burgdorferi; CRISPR/Cas technology; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Data; Detection; Development; Europe; Event; Fostering; Future; Generations; Genetic; Goals; Homeostasis; Human; Human Resources; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunobiology; Immunologic Deficiency Syndromes; In Vitro; Infection; Ingestion; Institution; Instruction; Invaded; Investigation; Ixodes; Janus kinase; Knowledge; Laboratories; Life Style; Lipids; Lyme Disease; Membrane; Methodology; Microbe; Molecular; Organism; Pathway interactions; Physiology; Plants; Prevalence; Program Research Project Grants; Reagent; Recording of previous events; Reporter; Research; Resources; Role; STAT protein; Scientist; Seeds; Shapes; Signal Pathway; Signal Transduction; Structure; Tick-Borne Infections; Ticks; Training; United States; Vector-transmitted infectious disease; cytokine; data resource; extracellular; genomic platform; gut microbiota; in vivo; innovation; microbial; microbiota; mouse model; neglect; outreach; pathogen; programs; tick feeding; tick-borne pathogen; tool; vector; Address; Anaplasma phagocytophilum; Anaplasmosis; Area; Biological; Biological Assay; Black-legged Tick; Blood; Borrelia burgdorferi; CRISPR/Cas technology; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Data; Detection; Development; Europe; Event; Fostering; Future; Generations; Genetic; Goals; Homeostasis; Human; Human Resources; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunobiology; Immunologic Deficiency Syndromes; In Vitro; Infection; Ingestion; Institution; Instruction; Invaded; Investigation; Ixodes; Janus kinase; Knowledge; Laboratories; Life Style; Lipids; Lyme Disease; Membrane; Methodology; Microbe; Molecular; Organism; Pathway interactions; Physiology; Plants; Prevalence; Program Research Project Grants; Reagent; Recording of previous events; Reporter; Research; Resources; Role; STAT protein; Scientist; Seeds; Shapes; Signal Pathway; Signal Transduction; Structure; Tick-Borne Infections; Ticks; Training; United States; Vector-transmitted infectious disease; cytokine; data resource; extracellular; genomic platform; gut microbiota; in vivo; innovation; microbial; microbiota; mouse model; neglect; outreach; pathogen; programs; tick feeding; tick-borne pathogen; tool; vector

OVERALL - Abstract The proposed Program Project (P01), entitled “Tick Immune Signaling, Microbiota, and Acquisition of Borrelia burgdorferi and Anaplasma phagocytophilum” aims to understand the molecular mechanisms by which the Ixodes tick immune system recognizes invading microbes, interfaces with resident gut microbiota, and impact pathogen persistence. We discovered two unorthodox tick immune cascades that are (a) involved in microbial recognition by an indirect “cross-kingdom” circuit triggered by a mammalian cytokine acquired in the vector blood meal, or (b) by a direct induction by specific bacterial lipids through an atypical immunodeficiency pathway. We also established that (c) interactions between tick gut microbiota and invading pathogens shape vector physiology and immunity, ultimately impacting the ability of ticks to acquire B. burgdorferi or A. phagocytophilum. Building on these paradigms and by combining the expertise and resources from four institutions with impressive history of research involving tick-borne infections, we will determine how discrete Ixodes tick immune pathways, either independently or synergistically, influence the entry and persistence of two major pathogens, B. burgdorferi and A. phagocytophilum. These microbes constitute the focus of our proposal due to their diverse structural and genetic features, their different lifestyles - either extracellular or intracellular - and the fact that they are responsible for the most prevalent tick-borne infections in the United States and many parts of Europe. This Program Project Grant leverages specific assays, tools and methodologies developed by our laboratories, who have a long history of productive collaboration, and which will be supported by an Administrative Core, and a Tick Resource Core whereby organisms and cell lines will be shared. The proposed aims to achieve the goals of this P01 are 1) Develop a Tick Core that provides the research reagents to all projects and to scientific community; 2) Determine how mammalian factors present in tick blood meal stimulate multiple cross-species immunity signaling pathways impacting persistence of diverse pathogens; 3) Investigate molecular basis of microbial detection in ticks via signaling relays and crosstalk by multiple immune pathways; 4) Examine interactions between tick immunome and gut microbiota and how these events impact persistence of tick-borne pathogens. Altogether, this proposal will increase our fundamental understanding of how tick immune signaling pathways operate and interface with the gut microbiota to influence the ability of diverse tick-borne pathogens to persist in the vector and subsequently infect the vertebrate host. The outreach activities generated by sharing the research data, and resources to the scientific community will plant new seeds of innovative research furthering our knowledge of tick-borne infections. Finally, with the technical and conceptual breakthroughs expected, the P01 will entice a new generation of scientists to be engaged and advance this important, yet neglected field of scientific research.

总体 - 抽象 拟议的计划项目（P01），标题为“ tick免疫信号传导，微生物群和获取 Borrelia burgdorferi和Anaplasma phocytophilum”的目的是通过了解分子机制 ixodes tick免疫系统识别出入侵的微生物，与居民肠道微生物群的接口， 并影响病原体的持久性。我们发现了两个非正统的tick免疫级联反应（a） 在微生物识别中，通过获得的哺乳动物细胞因子触发的间接“跨王朝”电路 矢量血粉，或（b）特定细菌通过非典型细菌直接诱导 免疫缺陷途径。我们还确定（c）tick肠菌和入侵之间的相互作用 病原体塑造了载体生理和免疫学，最终影响了滴答的获取能力。 burgdorferi或A. phocytophilum。以这些范式为基础，并结合专业知识和资源 从四个具有令人印象深刻的研究史的机构中，我们将确定如何确定 独立或协同的离散ixodes tick免疫途径会影响条目和 两种主要病原体的持久性，B。burgdorferi和A. phagocytophilum。这些微生物构成 我们的提案的重点是由于其潜水员的结构和遗传特征，他们的生活方式不同 - 要么 细胞外或细胞内 - 以及它们是最普遍的tick传播感染的事实 在美国和欧洲的许多地方。该计划项目授予利用特定的评估，工具 以及我们的实验室开发的方法，他们的产品协作历史悠久，并且 它将得到行政核心的支持，以及有机体和细胞的刻度资源核心 行将共享。拟议的目的是实现该P01的目标是1）开发一个壁虱核心 为所有项目和科学界提供研究试剂； 2）确定哺乳动物如何 tick血中存在的因素刺激多个跨物种免疫信号传导途径影响 多种病原体的持久性； 3）通过信号调查tick中微生物检测的分子基础 继电器和串扰多个免疫途径； 4）检查壁虱免疫组与肠道的相互作用 微生物群以及这些事件如何影响tick传播病原体的持久性。总之，这个建议将 提高我们对tick免疫信号通路如何运作并与之接口的基本了解 肠道微生物群会影响各种tick传播病原体在载体中持续存在的能力，随后 感染脊椎动物宿主。通过共享研究数据和资源来产生的外展活动 科学界将种植新的创新研究种子 感染。最后，随着技术和概念的突破，P01将吸引一个新的 一代科学家的参与并推进了这一重要但被忽视的科学研究领域。