Rickettsial Immunity During Tick Transmission

描述（由申请人提供）：长时间进食蜱虫会使几种传染性病原体传播给哺乳动物宿主。蜱虫唾液的抗炎特性促进了病原体的传播。虽然蜱虫唾液的非凡特性几十年来一直为人所知，但导致更有利的病原体传播环境的信号机制仍然难以捉摸。缺乏这种知识是有问题的，因为它妨碍了开发预防传染病的新疗法。在这个建议中，我们将了解蜱虫唾液蛋白，病原体和脊椎动物免疫系统的复杂相互作用。我们假设唾液抑素L2 -一种蜱唾液蛋白-调节炎性体的激活并促进立克次体病原体嗜吞噬细胞无原体向哺乳动物宿主的传播。炎症小体促进炎症细胞因子的成熟，并参与感染期间的宿主防御。我们已发表和未发表的数据表明，炎症小体对抗嗜吞噬胞杆菌的先天免疫很重要。我们还发现唾液抑素L2抑制炎性体的激活。我们将通过以下目的来验证我们的中心假设，即唾液抑制素L2促进了立克次体病原体嗜吞噬细胞芽胞杆菌向哺乳动物宿主的传播：(1)我们将定义在嗜吞噬细胞芽胞杆菌感染期间导致炎性体激活的信号通路；(2)我们将描述涎腺抑素L2在嗜吞噬单胞虫蜱传播过程中如何抑制炎性体激活。这一建议的结果范围非常广泛。蜱、蚊子、咬人的苍蝇、跳蚤和吸血的虫子已经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媒介-宿主-病原体关联的各种研究，从而对媒介传播疾病的发病机制和免疫产生新的认识。我们设想，破译节肢动物传播的病原体如何在哺乳动物宿主中定植，可能会导致针对许多节肢动物传播的疾病的新疗法。

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 Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum.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.