Tick Saliva and Pathogen Transmission

摘要/摘要：扁虱是一种食血性体外寄生虫，在全球范围内都有公共卫生和兽医方面的危害。 重要性。他们生命策略的成功可以部分归功于抗炎唾液蛋白。 抑制宿主免疫，促进病原体传播。举个例子，我们最近发现了一本小说 肩部硬蜱唾液蛋白Sialostatin L2抑制活化的免疫逃逸机制 NLRC4炎症性小体。NLRC4炎症体是一种蛋白质支架，调节细胞的成熟 促炎症细胞因子IL-1、β和IL-18通过caspase-1酶。我们证明了这一点 Sialostatin L2与哺乳动物宿主蛋白Annexin A2结合。感染立克次体病原体时 无浆体吞噬细胞，Sialostatin L2损害NLRC4炎症体的组装。如何记号效应器 在血液喂养过程中释放的分子，如Sialostatin L2，仍然是未知的。以什么方式 病原体，如吞噬细胞性嗜血杆菌，影响壁虱分子向哺乳动物宿主的传递。 难以捉摸。淋巴系统，循环血管的网络，是否提供了一种快速的机制 取血过程中的免疫学信息的传播仍未确定。外切体是 小的胞外小泡，在细胞间的通讯中起作用，促进宿主免疫调节。 对于这一R01应用，我们证明了一肩关节外体与宿主免疫细胞相互作用并运输 抗炎扁虱唾液蛋白。我们报告吞噬弧菌改变了细胞的氧化状态。 外体内的分子。最后，我们证明淋巴系统起到了管道的作用， 壁虱蛋白的释放可能会影响炎症。因此，我们的中心假设是淋巴管 在扁虱饲养过程中，系统在调节炎症方面起着关键作用；而外切体有助于 肩袖吸虫与哺乳动物寄主之间的相互联系。该提案的目标1将确定反 壁虱外切体内的炎性分子。Aim#2将在以下内容中定义氧化翻译后修饰 扁虱外切体。目的#3将评估淋巴系统在扁虱饲养过程中的作用。总而言之，这 研究将确定扁虱来源的外切体如何运输唾液蛋白；调查潜在的 吞噬细胞里氏立克次体病原体影响外体的机制；并揭示 淋巴系统携带扁虱衍生的分子。因为扁虱和其他节肢动物传播许多人类 病原体在进食过程中，解决这一有趣的科学问题将为病媒提供关键的见解 生物界。

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.