Tick feeding regulation by orthologous tick saliva serine protease inhibitors

直系同源蜱唾液丝氨酸蛋白酶抑制剂对蜱摄食的调节

• 批准号: 8087210
• 负责人: ALBERT MULENGA
• 金额: $ 24.87万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087210
• 关键词: Adult; Amblyomma; Amino Acids; Antibodies; Antibody Formation; Anticoagulants; Antigen Targeting; Antigens; Arthropod Vectors; Babesiosis; Basophils; Biological Assay; Black-legged Tick; Blood; Blood coagulation; Bovine Anaplasmosis; Cathepsin G; Cells; Chymase; Complement Activation; Containment; Data; Deer; Development; Ehrlichia chaffeensis; Ehrlichiosis; Enzyme-Linked Immunosorbent Assay; Exanthema; Future; Gene Bank; Goals; Harvest; Host Defense; Human; Immunity; Immunization; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Leukocyte Elastase; Lyme Disease; Mediating; Methods; Natural Immunity; Nature; Nymph; Orthologous Gene; Pathway interactions; Physiology; Protein Sequence Analysis; Proteinase 3; Proteins; Protocols documentation; Proxy; Reaction; Recombinants; Regulation; Research; Ricinus plant; Role; Saliva; Salivary Glands; Secondary Immunization; Serine Protease; Serine Proteinase Inhibitors; Site; Tail; Tick Control; Tick Infestations; Tick-Borne Diseases; Ticks; Tryptase; United States; Vaccines; Validation; Vector-transmitted infectious disease; Western Blotting; acaricide; base; defense response; feeding; mast cell; new technology; prevent; programs; success; synthetic peptide

DESCRIPTION (provided by applicant): In the United States human vector borne diseases are primarily tick borne. The goals of this research are identification, characterization and validation of Amblyomma americanum and Ixodes scapularis tick saliva serine protease inhibitors (serpins) as vaccine target antigens for immunization of white tailed deer against tick infestation. To complete feeding, ticks must overcome host defense reactions, blood coagulation, complement activation and inflammation, all of which are serine protease mediated pathways that are tightly controlled by serpins. Our lab and others have proposed that during feeding, ticks express and inject serpins into the host to regulate evasion of host defense response to tick feeding activity. In an ongoing NIHR03 project in its final year we have screened 10 A. americanum (Aam) tick salivary gland (SG) serpin, and validated that 2 of the serpins (S), AamS6 and AamS8 are secreted into tick saliva, which is proxy for their injection into the host during tick feeding. We have extended these studies and identified 14 blood meal responsive I. scapularis tick SG serpins. In this proposal we will utilize protocols developed in the NIHR03 project to validate secretion of the 14 I. scapularis SG serpins into tick saliva. We have observed that the two A. americanum tick saliva serpins as well as the I. ricinus tick saliva serpin are highly conserved in ticks. Thus, we hypothesize that ticks utilize orthologous tick saliva serpins to regulate tick feeding and that immunologically blocking tick saliva serpin functions will prevent feeding success of multiple tick species. The importance of white tailed deer (Odocoileus virginianus) in the emergence of major human tick borne diseases (TBD) in the United States, Lyme disease, human anaplasmosis, babesiosis and ehrlichiosis and the southern tick-associated rash illness (STARI) has been recognized. Thus data in this proposal will be directly relevant towards efforts to develop novel technologies to prevent human TBD. There are 3 specific aims in this application. The first is to validate secretion of 16 blood meal responsive I. scapularis tick salivary gland serpins into tick saliva. The second is to characterize role(s) of A. americanum and I. scapularis native tick saliva serpins in tick feeding regulation. To validate tick immunity and anamnestic antibody response to tick infestation of white tailed deer immunized with recombinant tick saliva serpin antigens. PUBLIC HEALTH RELEVANCE: In the United States ticks transmit more vector borne disease agents than any other vector arthropod. Limitations associated with current acaricide based tick control strategies that threaten the future sustainability of containment programs for tick borne illnesses, have necessitated the need for development of alternative tick control strategies. Identification of important tick proteins that regulate tick physiology and facilitate tick feeding is important before alternative tick control methods can be developed.

描述（由申请人提供）：在美国，人类媒介传播的疾病主要是蜱传播的。本研究的目标是鉴定、表征和验证美洲钝蜱和肩胛硬蜱蜱唾液丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）作为白尾鹿免疫接种蜱虫感染的疫苗靶抗原。为了完成摄食，蜱必须克服宿主防御反应、凝血、补体激活和炎症，所有这些都是丝氨酸蛋白酶介导的途径，受到丝氨酸蛋白酶抑制剂的严格控制。我们的实验室和其他人提出，在进食过程中，蜱虫表达丝氨酸蛋白酶抑制剂并将其注射到宿主体内，以调节宿主对蜱虫进食活动的防御反应的逃避。在正在进行的 NIHR03 项目的最后一年中，我们筛选了 10 个美洲蜱 (Aam) 蜱唾液腺 (SG) 丝氨酸蛋白酶抑制剂，并验证了其中 2 个丝氨酸蛋白酶抑制剂 (S)、AamS6 和 AamS8 被分泌到蜱唾液中，这是代理在蜱虫进食期间将其注射到宿主体内。我们扩展了这些研究并鉴定了 14 种血粉反应性肩胛伊氏蜱 SG 丝氨酸蛋白酶抑制剂。在本提案中，我们将利用 NIHR03 项目中开发的方案来验证 14 个 I. scapularis SG 丝氨酸蛋白酶抑制剂分泌到蜱唾液中。我们观察到两种美洲蜱唾液丝氨酸蛋白酶抑制剂和蓖麻蜱唾液丝氨酸蛋白酶抑制剂在蜱中高度保守。因此，我们假设蜱利用直系同源蜱唾液丝氨酸蛋白酶抑制剂来调节蜱摄食，并且免疫阻断蜱唾液丝氨酸蛋白酶抑制剂功能将阻止多种蜱物种的摄食成功。白尾鹿 (Odocoileus virginianus) 在美国主要人类蜱传疾病 (TBD)、莱姆病、人类无形体病、巴贝斯虫病和埃利希体病以及南方蜱相关皮疹病 (STARI) 的出现中的重要性已得到认识。因此，本提案中的数据将直接与开发预防人类 TBD 的新技术相关。该应用程序有 3 个具体目标。第一个是验证 16 种血粉反应性肩胛蜱唾液腺丝氨酸蛋白酶抑制剂分泌到蜱唾液中。第二个是描述美洲蜱和肩胛蜱本地蜱唾液丝氨酸蛋白酶抑制剂在蜱摄食调节中的作用。验证用重组蜱唾液丝氨酸蛋白酶抑制剂抗原免疫的白尾鹿的蜱免疫和记忆抗体对蜱感染的反应。 公共卫生相关性： 在美国，蜱传播的媒介传播疾病比任何其他媒介节肢动物都多。当前基于杀螨剂的蜱虫控制策略的局限性威胁着蜱传疾病遏制计划未来的可持续性，因此需要开发替代的蜱虫控制策略。在开发替代蜱虫控制方法之前，鉴定调节蜱虫生理学和促进蜱虫进食的重要蜱虫蛋白非常重要。