Rickettsial Immunity During Tick Transmission

蜱传播期间的立克次体免疫

• 批准号: 8192073
• 负责人: Joao Pedra
• 金额: $ 36.68万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192073
• 关键词: Address; Affect; Anaplasma phagocytophilum; Anti-Inflammatory Agents; Anti-inflammatory; Arthropods; Biology; Bite; Blood; Bovine Anaplasmosis; Caspase-1; Cells; Chronic; Clinical Trials; Communicable Diseases; Communities; Complex; Culicidae; Data; Development; Disease; Environment; Enzymes; Fleas; Goals; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Infectious Agent; Inflammatory; Interleukins; Knowledge; Lead; Literature; Microbiology; Modeling; Mus; Names; Natural Immunity; Outcome; Pathogenesis; Pathway interactions; Preventive; Process; Property; Publications; Publishing; Research; Research Personnel; Rickettsia Infections; Saliva; Salivary Proteins; Signal Pathway; Signal Transduction; Staging; Study Section; Testing; Therapeutic; Tick-Borne Diseases; Ticks; United States; Vector-transmitted infectious disease; base; cytokine; feeding; fly; immunoregulation; macrophage; microbial; novel; novel therapeutics; pathogen; prevent; receptor; transmission process; unpublished works; vaccine development; vector

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 Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum.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. PUBLIC HEALTH RELEVANCE: Our application will define mechanistically how a tick salivary protein inhibits the host immune response during pathogen infection. The information gained from this application will provide a novel immunological concept that may be applied to the development of vaccines against rickettsial diseases.

描述（由申请人提供）：tick的长时间喂养使几种传染剂传播给哺乳动物宿主。 TICK唾液的抗炎特性促进了tick病原体传播。虽然tick唾液的非凡特性数十年来一直闻名，但导致病原体传播环境更有利的信号传导机制仍然难以捉摸。缺乏这种知识是有问题的，因为它排除了预防传染病的新疗法的发展。在此提案中，我们将了解tick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Sialostatin L2（tick唾液蛋白）调节炎性体激活并促进立克乳突病原体的吞噬吞噬细胞吞噬型的转移向哺乳动物宿主。炎性体促进炎性细胞因子的成熟，并在感染过程中参与宿主防御。我们发表的未发表的数据表明，炎性体对于对吞噬大麻的先天免疫力很重要。我们还表明，唾液抑素L2抑制了炎性体的激活。我们将测试我们的核心假设，即唾液酸抑制素L2通过追求以下目的来促进立克菌病原体的吞噬细胞嗜血杆菌向哺乳动物宿主传播：（1）我们将定义信号传导途径，从而导致吞噬细胞嗜酸杆菌感染期间炎症体激活的信号途径； （2）我们将表征Sialostatin L2如何抑制吞噬吞噬细胞杆菌的tick传播过程中的炎症体激活。该提议的结果在范围上显着宽。壁虱，蚊子，咬蝇，跳蚤和喂食虫子已经进化了唾液蛋白来调节宿主防御。因此，我们的发现可能会刺激对各种载体 - 托管病原体关联的研究，从而对媒介传播疾病的发病机理和免疫力进行新的理解。我们设想那种破译是如何将哺乳动物宿主定居的节肢动物传播的病原体可能导致针对许多节肢动物传播疾病的新疗法。 公共卫生相关性：我们的应用将从机械上定义滴答唾液蛋白如何抑制病原体感染期间宿主免疫反应。从本应用中获得的信息将提供一种新颖的免疫学概念，可以应用于针对立克疾病的疫苗开发。