Tick-Pathogen Interactions: Exploring the Intersection between Stress Responses and Immunity

蜱-病原体相互作用：探索应激反应与免疫之间的交叉点

基本信息

批准号：
10521653
负责人：
Dana Kathleen Shaw
金额：
$ 53.55万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-11 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521653
关键词：
Address Anaplasma phagocytophilum Anaplasmosis Animal Model Arbovirus Infections Arthropod Vectors Arthropods Bacteria Biology Black-legged Tick Borrelia burgdorferi Case Study Cell Line Cellular Stress Response Centers for Disease Control and Prevention (U.S.)Data Disease Disease Vectors Drosophila genus Drosophila melanogaster Eukaryota Event Funding Genes Genetic Transcription Growth Host Defense Human Immune Immune system Immunity Immunologic Receptors In Vitro Infection Infectious Agent Insecta Kinetics Knowledge Label Lyme Disease Mediating Microbe Molecular Morbidity - disease rate Natural Immunity Pathway interactions Pattern Pattern recognition receptor Pharmacology Process Proteins RNA Interference Research Personnel Role Signal Transduction Source Stress Study Section System TRAF2 gene Testing Ticks Tissues Transcriptional Activation United States Universities Vector-transmitted infectious disease Washington base biological adaptation to stress comparative granulocyte in vivo knock-down microbial migration mortality novel pathogen pathogenic bacteria response stressor tick transmission tick-borne transcription factor transmission process vector vector competence

项目摘要

Abstract Arthropod-borne disease continues to be a significant source of morbidity and mortality worldwide. The ability of an arthropod to harbor and transmit pathogens is termed “vector competency”. Many factors influence vector competency, including how the arthropod immune system responds to the microbe. The intricacies of insect immunity have been well-studied owing the model organism, Drosophila. In contrast, comparatively little is known about tick immunity, representing a fundamental knowledge gap in vector biology. Arthropod immune processes are now increasingly recognized as being divergent across species. For example, we identified a noncanonical Immune Deficiency (IMD) pathway in ticks that limits colonization of two bacterial pathogens: Borrelia burgdorferi (Lyme disease) and Anaplasma phagocytophilum (Human Granulocytic Anaplasmosis). Ticks lack genes encoding upstream IMD pathway regulators. Therefore, the molecular and cellular events preceding the noncanonical IMD pathway in ticks deviate from the classical paradigm defined in insects. We asked in our previously funded R21 whether a specialized stress-response system termed the Unfolded Protein Response (UPR) could impact vector competency through tick immunity. Infection imparts stress on the host and, for this reason, cellular stress-responses are tightly intertwined with innate immunity. Our data shows that the UPR is induced by tick-borne bacteria and initiates the noncanonical IMD pathway in ticks. Through RNAi knockdown and pharmacological manipulation, we show that the IRE1α branch of the UPR signals through the adapter molecule TRAF2 to restrict vector colonization by A. phagocytophilum and B. burgdorferi both in vitro and in vivo. Collectively, our findings provide an explanation for how the core IMD pathway is activated independent of canonical upstream regulators. Based on these findings, our central hypothesis is that the UPR functionally regulates vector-microbe interactions through crosstalk with the IMD pathway. AIM 1 of this proposal will now investigate the role of the I. scapularis UPR on microbial growth, migration kinetics through tick tissues and/or transmission to a naïve host. AIM 2 will uncover the mechanistic linkage between the UPR and the noncanonical IMD pathway using an unbiased approach to define and characterize the signalosome during infection. Since microbial infections impart stress on host systems and cellular stress responses are well conserved across eukaryotes, we expect that the findings from this R01 will uncover novel determinants of vector competence and may have broad relevance to many arthropod-pathogen systems.

抽象的节肢动物传播的疾病仍然是全世界发病率和死亡率的重要来源。节肢动物藏匿和传播病原体的能力被称为“媒介能力”，影响媒介的因素有很多。能力，包括节肢动物免疫系统如何对微生物做出反应昆虫的复杂性。由于模式生物果蝇，免疫已经得到了充分的研究，相比之下，人们对免疫的了解相对较少。关于蜱免疫，代表了节肢动物免疫过程的基本知识差距。现在越来越多地认识到不同物种之间存在差异，例如，我们发现了一个非规范的。蜱虫中的免疫缺陷 (IMD) 途径限制了两种细菌病原体的定植：伯氏疏螺旋体 (Borrelia burgdorferi) （莱姆病）和嗜吞噬细胞无形体（人类粒细胞无形体病）缺乏基因。编码上游 IMD 通路调节因子因此，先于分子和细胞事件。蜱虫中的非典型 IMD 途径偏离了昆虫中定义的经典范式。先前资助的 R21 是否是一种称为“未折叠蛋白质反应”的专门应激反应系统（UPR）可能会通过蜱免疫影响媒介能力，从而给宿主带来压力。因此，细胞应激反应与先天免疫紧密相连。我们的数据表明，UPR 与先天免疫密切相关。由蜱传细菌诱导，并通过 RNAi 敲低启动蜱中的非典型 IMD 途径。和药理学操作，我们表明 UPR 信号的 IRE1α 分支通过适配器 TRAF2 分子在体外和体内限制嗜吞噬细胞放线菌和伯氏疏螺旋体的载体定植。总的来说，我们的研究结果解释了核心 IMD 通路如何独立于基于这些发现，我们的中心假设是 UPR 具有功能。现在将通过与该提案的 AIM 1 的串扰来调节载体-微生物相互作用。研究 I. scapularis UPR 对微生物生长、通过蜱组织的迁移动力学和/或传输到天真的主机 AIM 2 将揭示 UPR 和非规范之间的机械联系。 IMD 途径使用公正的方法来定义和表征感染过程中的信号体。微生物感染会给宿主系统带来压力，并且细胞应激反应在各个系统中都得到了很好的保守真核生物，我们期望 R01 的发现将揭示载体能力的新决定因素和可能与许多节肢动物病原体系统具有广泛的相关性。