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

总体-摘要 拟议的计划项目（P01），题为“蜱免疫信号，微生物群，和收购的 Borrelia burgdorferi and Anaplasma phagocytophilum”旨在通过以下途径了解其分子机制： 硬蜱的免疫系统识别入侵的微生物，与肠道微生物接触， 并影响病原体的持久性我们发现了两个非正统的蜱免疫级联反应， 在通过间接的“跨界”回路的微生物识别中， 载体血粉，或（B）通过特异性细菌脂质通过非典型的 免疫缺陷途径。我们还确定了（c）蜱肠道微生物群和入侵之间的相互作用 病原体塑造媒介生理和免疫，最终影响蜱获得B的能力。 burgdorferi或A.嗜吞噬细胞菌在这些范例的基础上， 从四个机构与蜱传感染的研究令人印象深刻的历史，我们将确定如何 离散硬蜱蜱免疫途径，无论是独立或协同，影响进入和 两种主要病原体的持续存在，B. burgdorferi和A.嗜吞噬细胞菌这些微生物构成了 由于他们不同的结构和遗传特征，他们不同的生活方式-无论是 细胞外或细胞内-事实上，他们是负责最普遍的蜱传感染 在美国和欧洲的许多地方。该计划项目赠款利用特定的测定，工具， 和我们的实验室开发的方法，他们有着悠久的生产合作历史， 它将由一个管理核心和一个蜱虫资源核心支持， 线路将共享。为实现本P01的目标，建议的目标是：1）开发一个Tick Core， 为所有项目和科学界提供研究试剂; 2）确定哺乳动物 蜱血粉中存在的因子刺激多种跨物种免疫信号传导途径， 不同病原体的持久性; 3）通过信号传导研究蜱中微生物检测的分子基础 通过多种免疫途径的中继和串扰; 4）检查蜱免疫组和肠道之间的相互作用 微生物群以及这些事件如何影响蜱传病原体的持久性。总的来说，这项建议将 增加我们对蜱免疫信号通路如何运作以及与 肠道微生物群影响多种蜱传病原体在载体中持续存在的能力， 感染脊椎动物宿主通过分享研究数据和资源， 科学界将播下创新研究的新种子， 感染.最后，随着技术和概念上的突破，P01将吸引一个新的 这是一个非常重要的问题，需要一代科学家参与并推进这一重要但被忽视的科学研究领域。

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.