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; 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.

抽象的 节肢动物传播疾病仍然是全球发病率和死亡率的重要来源。能力 港口和传输病原体的节肢动物称为“矢量能力”。许多因素影响向量 能力，包括节肢动物免疫系统对微生物的反应。昆虫的复杂性 由于模型生物果蝇，免疫力已得到充分研究。相比之下，相对鲜为人知 关于tick免疫，代表媒介生物学的基本知识差距。节肢动物免疫过程 现在越来越多地被认为是各种各样的分歧。例如，我们确定了一个非规范的 tick中的免疫缺陷（IMD）途径限制了两种细菌病原体的定殖：Borrelia burgdorferi （莱姆病）和吞噬吞噬细胞（人粒细胞无质膜）。壁虱缺乏基因 编码上游IMD路径调节器。因此，之前的分子和细胞事件 tick中的非规范IMD途径偏离昆虫定义的经典范式。我们问我们 先前资助的R21是否称为未折叠蛋白反应的专门应力反应系统 （UPR）可能会通过tick免疫影响向量的能力。感染对宿主的压力，为此 原因，细胞应力反应与先天免疫紧密地交织在一起。我们的数据表明UPR是 由tick传播细菌诱导，并在壁虱中启动非规范IMD途径。通过RNAi敲除 和药理操作，我们表明UPR信号的IRE1α分支通过适配器 分子traf2在体外和体内限制了吞噬细胞杆菌和B. burgdorferi的载体定植。 总的来说，我们的发现提供了一个解释核心IMD途径如何独立激活的解释 规范上游调节器。基于这些发现，我们的中心假设是UPR在功能上 通过与IMD途径的串扰来调节矢量微粒相互作用。该提案的目标1现在将 研究肩capularis UPR对微生物生长的作用，通过壁虱组织和/或 传输到幼稚的主人。 AIM 2将揭示UPR与非规范性之间的机械联系 IMD途径采用公正的方法来定义和表征感染过程中信号体的表征。自从 微生物感染给宿主系统带来了压力，细胞应力反应在整个 真核生物，我们希望R01的发现将发现新颖的媒介能力和 可能与许多节肢动物 - 病原体系统具有广泛的相关性。