Tick Saliva and Pathogen Transmission

蜱唾液和病原体传播

• 批准号: 10394207
• 负责人: Joao Pedra
• 金额: $ 55.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394207
• 关键词: Address; Affect; Anaplasma phagocytophilum; Annexins; Anti-Inflammatory Agents; Antigens; Area; Arthropod Vectors; Arthropods; Baltimore; Binding; Biological Markers; Biology; Black-legged Tick; Blood; Borrelia burgdorferi; CASP1 gene; Cells; Communicable Diseases; Communities; Data; Defect; Dendritic Cells; Enzyme Activation; Enzymes; Exhibits; Family; Growth; Homeostasis; Hour; Immune; Immune Evasion; Immune Targeting; Immune signaling; Immunity; Immunologics; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Ixodes; Laboratories; Life; Location; Lymphatic; Lymphatic System; Maryland; Medicine; Mus; New York City; Oxidative Stress; Pathway interactions; Play; Post-Translational Protein Processing; Principal Investigator; Process; Proteins; Public Health; Publishing; RNA Interference; Reporting; Research; Research Personnel; Rickettsia; Role; Salivary; Salivary Proteins; Scaffolding Protein; Skin; System; Testing; Tick-Borne Diseases; Ticks; Training; Universities; Vaccines; arthropod-borne; authority; base; college; cytokine; density; exosome; extracellular vesicles; feeding; human pathogen; immunoregulation; insight; intercellular communication; medical schools; microbial; mid-career faculty; novel; pathogen; professor; response; success; tick feeding; tick saliva; transmission process; vector

Summary/Abstract: Ticks are hematophagous ectoparasites with worldwide public health and veterinary importance. The success of their life strategy can be attributed, in part, to anti-inflammatory salivary proteins that inhibit host immunity and facilitate pathogen transmission. As an example, we recently discovered a novel mechanism of immune evasion by which the Ixodes scapularis salivary protein Sialostatin L2 inhibits activation of the NLRC4 inflammasome. The NLRC4 inflammasome is a protein scaffold that regulates maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 through the enzyme caspase-1. We demonstrated that Sialostatin L2 binds to the mammalian host protein Annexin A2. Upon infection with the rickettsial pathogen Anaplasma phagocytophilum, Sialostatin L2 impairs assembly of the NLRC4 inflammasome. How tick effector molecules, such as Sialostatin L2, are released during blood-feeding continues to be unknown. In what manner pathogens, such as A. phagocytophilum, influence the delivery of tick molecules to the mammalian host remain elusive. Whether the lymphatic system, a network of circulatory vessels, provides a rapid mechanism of dissemination for immunological information during tick blood-feeding remains undetermined. Exosomes are small extracellular vesicles that function in intercellular communication, facilitating host immune modulation. For this R01 application, we show that I. scapularis exosomes interact with host immune cells and transport anti-inflammatory tick salivary proteins. We report that A. phagocytophilum alters the oxidative state of molecules within exosomes. Finally, we demonstrate that the lymphatic system acts as a conduit where the release of tick proteins may affect inflammation. Accordingly, our central hypothesis states that the lymphatic system plays a critical role in modulating inflammation during tick feeding; and that exosomes facilitate intercommunication between I. scapularis and the mammalian host. Aim#1 of this proposal will identify anti- inflammatory molecules within tick exosomes. Aim#2 will define oxidative post-translational modifications within tick exosomes. Aim#3 will evaluate the role of the lymphatic system during tick feeding. Altogether, this research will determine how tick-derived exosomes transport salivary proteins; investigate the underlying mechanisms by which the rickettsial pathogen A. phagocytophilum affects exosomes; and reveal whether the lymphatic system carries tick-derived molecules. As ticks and other arthropods transmit many human pathogens during feeding, solving this intriguing scientific question will provide critical insights to the vector biology community.

摘要/摘要：tick是造血型外寄生虫，具有全球公共卫生和兽医 重要性。他们的生活策略的成功可以部分归因于抗炎唾液蛋白 抑制宿主的免疫力并促进病原体传播。例如，我们最近发现了一部小说 免疫进化的机制，ixodes capularis唾液蛋白sialostatin L2抑制激活 NLRC4炎性体。 NLRC4炎性体是一种蛋白质支架，可调节 促炎性细胞因子白介素（IL）-1β和IL-18通过酶caspase-1。我们证明了这一点 Sialostatin L2与哺乳动物宿主蛋白膜联蛋白A2结合。感染后立克病原体 Anaplasma吞噬细胞，sialostatin L2损害NLRC4炎症体的组装。滴答效应器 在血液喂养期间释放的分子，例如唾液抑素L2，尚不清楚。以什么方式 病原体，例如吞噬细胞嗜酸杆菌，会影响tick分子向哺乳动物宿主的递送 难以捉摸。淋巴系统是电路容器网络是否提供了一种快速机制 在滴答滴答过程中以获取免疫信息的传播仍未确定。外泌体是 在细胞间通信中起作用的小细胞外蔬菜，支持宿主免疫调节。 对于此R01应用，我们表明I.肩cap骨外泌体与宿主免疫细胞相互作用并运输 抗炎滴答唾液蛋白。我们报告说，吞噬细胞藻会改变的氧化状态 外泌体内的分子。最后，我们证明淋巴系统是一个导管 tick蛋白的释放可能会影响炎症。根据所有人，我们的中心假设指出淋巴 系统在调节进食过程中调节注射方面起着至关重要的作用；外泌体设施 肩cap骨和哺乳动物宿主之间的互通。本提案的目标＃1将确定 tick外泌体内的炎症分子。 AIM＃2将定义氧化后翻译后修饰 滴答外泌体。 AIM＃3将评估在滴答过程中淋巴系统的作用。总共，这个 研究将决定滴答滴答的外泌体如何运输唾液蛋白；调查基础 立克病原体A.吞噬细胞影响外泌体的机制；并揭示了是否 淋巴系统携带tick衍生的分子。随着壁虱和其他节肢动物传播许多人 喂养过程中的病原体，解决这个有趣的科学问题将为矢量提供关键的见解 生物学社区。