Tick Saliva and Pathogen Transmission

蜱是一种吸血性体外寄生虫，在世界范围内具有公共卫生和兽医学意义。 重要性他们的生存策略的成功可以部分归功于抗炎的唾液蛋白 抑制宿主免疫力并促进病原体传播。举个例子，我们最近发现了一本小说 肩突硬蜱唾液蛋白Sialostatin L2抑制激活的免疫逃避机制 NLRC 4炎性小体NLRC 4炎性体是一种蛋白质支架，调节细胞的成熟， 促炎细胞因子白细胞介素（IL）-1β和IL-18通过酶半胱天冬酶-1。我们证明了 唾液酸抑制素L2与哺乳动物宿主蛋白膜联蛋白A2结合。一旦感染立克次体病原体 嗜吞噬细胞无形体，唾液抑素L2损害NLRC 4炎性小体的组装。如何蜱效应器 分子，如Sialostatin L2，在血液喂养过程中释放仍然是未知的。以何种方式 病原体，如A.嗜吞噬细胞菌，影响蜱分子向哺乳动物宿主的传递， 难以捉摸。淋巴系统，一个循环血管网络，是否提供了一个快速的机制， 蜱吸血期间免疫学信息的传播仍不确定。外来体是 在细胞间通讯中起作用的小的细胞外囊泡，促进宿主免疫调节。 对于这个R 01应用程序，我们表明，我。肩胛骨外泌体与宿主免疫细胞相互作用并转运 抗炎蜱唾液蛋白。本文报道了A.嗜吞噬细胞菌改变了 外泌体中的分子。最后，我们证明了淋巴系统作为一个管道， 蜱蛋白的释放可能影响炎症。因此，我们的中心假设认为， 系统在调节蜱虫进食期间的炎症中起着关键作用;并且外泌体促进 I之间的交流。肩胛肌和哺乳动物宿主。该提案的目标1将确定反 蜱外来体中的炎症分子。目标#2将定义氧化翻译后修饰， 蜱外来体目标3将评价淋巴系统在蜱虫进食期间的作用。总之，这 研究将确定蜱源性外泌体如何转运唾液蛋白;调查潜在的 立克次体病原体A.嗜吞噬细胞菌影响外泌体;并揭示是否 淋巴系统携带蜱虫衍生的分子。由于蜱虫和其他节肢动物将许多人类 在喂养过程中的病原体，解决这个有趣的科学问题将提供关键的见解， 生物社区

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.