Rickettsial Immunity During Tick Transmission

描述(申请人提供)：长期喂食扁虱可使几种感染性病原体传播给哺乳动物宿主。扁虱唾液的抗炎特性促进了扁虱的病原体传播。虽然扁虱唾液的非凡特性早在几十年前就已为人所知，但导致病原体传播更有利环境的信号机制仍然难以捉摸。缺乏这种知识是有问题的，因为它阻碍了预防传染病的新疗法的开发。在这项提案中，我们将了解扁虱唾液蛋白、病原体和脊椎动物免疫系统之间的复杂相互作用。我们假设唾液蛋白唾液蛋白sialostatin L2调节炎性小体激活，并促进立克次体病原体吞噬无形体向哺乳动物宿主的传播。炎性小体促进炎性细胞因子的成熟，并在感染期间参与宿主防御。我们已发表和未发表的数据表明，炎性小体对于对抗吞噬细胞金黄色葡萄球菌的先天免疫是重要的。我们还表明，唾液酸抑制素L2抑制炎症体的激活。我们将通过追求以下目标来检验我们的中心假设：sialostatin L2通过追求以下目标来促进吞噬立克次体病原体向哺乳动物宿主的传播：(1)我们将定义在吞噬细胞性立克次体感染过程中导致炎症体激活的信号通路；以及(2)我们将表征sialostatin L2如何在扁虱传播吞噬细胞致病菌的过程中抑制炎性肌小体的激活。这项提议的结果在范围上非常广泛。扁虱、蚊子、叮咬的苍蝇、跳蚤和食血虫进化出唾液蛋白来调节宿主的防御。因此，我们的发现可能会刺激对一系列不同的媒介-宿主-病原体关联的研究，从而对媒介传播疾病的发病机制和免疫机制产生新的理解。我们预计，破译节肢动物传播的病原体是如何定植在哺乳动物宿主上的，可能会导致许多节肢动物传播疾病的新疗法。

DESCRIPTION (provided by applicant): Prolonged feeding of ticks enables the transmission of several infectious agents to the mammalian host. Pathogen transmission by ticks is facilitated by the anti-inflammatory properties of tick saliva. While the extraordinary properties of tick saliva have been known for decades, the signaling mechanisms that lead to a more favorable environment for pathogen transmission remain elusive. The lack of such knowledge is problematic because it precludes the development of novel therapies for preventing infectious diseases. In this proposal, we will understand the complex interplay of a tick salivary protein, a pathogen and the vertebrate immune system. We hypothesize that sialostatin L2 - a tick salivary protein - modulates inflammasome activation and facilitates transmission of the rickettsial pathogen Anaplasma phagocytophilum to a mammalian host. The inflammasome promotes the maturation of inflammatory cytokines and is involved in host defense during infection. Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum. We also show that sialostatin L2 inhibits inflammasome activation. We will test our central hypothesis that sialostatin L2 facilitates transmission of the rickettsial pathogen A. phagocytophilum to a mammalian host by pursuing the following aims: (1) we will define signaling pathways that lead to inflammasome activation during A. phagocytophilum infection; and (2) we will characterize how sialostatin L2 inhibits inflammasome activation during tick transmission of A. phagocytophilum. The outcome of this proposal is significantly wide in scope. Ticks, mosquitoes, biting flies, fleas and blood feeding bugs have evolved salivary proteins to modulate host defense. Therefore, our findings may stimulate research into a diverse array of vector-host-pathogen associations resulting in new understandings of pathogenesis and immunity of vector-borne diseases. We envisage that deciphering how arthropod-borne pathogens colonize the mammalian host may lead to novel therapeutics against many arthropod borne diseases.