Rickettsial Immunity During Tick Transmission

性状（由申请方提供）：长时间喂食蜱虫可将几种传染性病原体传播给哺乳动物宿主。蜱唾液的抗炎特性促进了蜱的病原体传播。虽然蜱唾液的非凡特性已经被发现了几十年，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，因为它妨碍了预防传染病的新疗法的开发。在这个建议中，我们将了解蜱唾液蛋白，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 -蜱唾液蛋白-调节炎性小体激活，并促进立克次体病原体无形体嗜吞噬细胞的哺乳动物宿主的传输。炎性小体促进炎性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，炎性小体是重要的天然免疫对A。嗜吞噬细胞菌我们还表明，唾液酸抑制素L2抑制炎性小体激活。我们将检验我们的中心假设，即唾液酸抑制素L2促进立克次体病原体A的传播。通过追求以下目标，我们将确定导致A.嗜吞噬细胞菌感染;（2）我们将描述唾液抑素L2如何抑制蜱传播A.嗜吞噬细胞菌这一建议的结果范围很广。蜱、蚊子、叮咬苍蝇、跳蚤和吸血虫已经进化出唾液蛋白来调节宿主防御。因此，我们的研究结果可能会刺激研究到一个不同的数组的媒介-宿主-病原体协会导致新的理解的发病机制和免疫的媒介传播疾病。我们设想，破译节肢动物传播的病原体如何定殖哺乳动物宿主可能会导致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 Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum.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.