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

• 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
• 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

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.

摘要 节肢动物传播的疾病仍然是全世界发病率和死亡率的一个重要来源。的能力 节肢动物窝藏和传播病原体被称为“媒介能力”。影响矢量的因素很多 能力，包括节肢动物免疫系统如何对微生物作出反应。昆虫的复杂性 由于模式生物果蝇，免疫已经得到了很好的研究。相比之下， 关于蜱虫免疫力，代表了病媒生物学的一个基本知识空白。节肢动物免疫过程 现在越来越多地被认为是不同物种的差异。例如，我们发现了一个非典型的 蜱中限制两种细菌病原体定殖的免疫缺陷（IMD）途径：伯氏疏螺旋体 (Lyme疾病）和嗜吞噬细胞无形体（人粒细胞无形体病）。蜱虫缺乏基因 编码上游IMD通路调节剂。因此，细胞分裂之前的分子和细胞事件 蜱中的非经典IMD途径偏离了昆虫中定义的经典范式。我们要求在我们的 先前资助的R21是否是一个专门的应激反应系统，称为未折叠蛋白质反应 (UPR)可以通过蜱虫免疫力影响病媒能力。感染会给宿主带来压力， 因此，细胞应激反应与先天免疫密切相关。我们的数据显示，普遍定期审议是 由蜱传细菌诱导，并启动蜱中的非经典IMD途径。通过RNAi敲除 和药理学操作，我们表明，IRE 1 α分支的UPR信号通过适配器 分子TRAF 2限制A.嗜吞噬细胞菌和B. Burgdorferi在体外和体内。 总的来说，我们的研究结果为核心IMD通路如何独立于 规范的上游调节器。基于这些发现，我们的中心假设是，普遍定期审议在功能上 通过与IMD途径的串扰调节载体-微生物相互作用。该提案的AIM 1现在将 研究了I.肩胛骨UPR对微生物生长、通过蜱组织的迁移动力学和/或 传播给天真的宿主。AIM 2将揭示普遍定期审议和非规范之间的机制联系 IMD通路使用无偏的方法来定义和表征感染期间的信号体。以来 微生物感染对宿主系统产生应激，细胞应激反应在整个宿主系统中保持良好。 真核生物，我们期望R 01的发现将揭示载体能力的新决定因素， 可能与许多节肢动物病原体系统有广泛的相关性。