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Molecular Mechanisms Regulating Early Stage Tick Feeding

调节早期蜱摄食的分子机制

基本信息

批准号：
8212177
负责人：
ALBERT MULENGA
金额：
$ 21.59万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-13 至 2014-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In the United States reported human vector-borne diseases are primarily tick-borne. For continued cycling of tick-borne disease pathogens in nature, successful tick feeding is required. Molecular mechanisms that regulate early stage tick feeding are poorly defined. They are critical to understanding the acquisition and transmission of pathogens by ticks, which in turn will be important in designing novel approaches to control ticks and tick- borne diseases. The goal of this proposal is molecular identification and target validation of Amblyomma americanum tick saliva proteins that are injected into the host during the first 48 h of tick feeding. The rationale to focus on this time point is that, it precedes the key facets of tick feeding, blood meal up take and tick borne disease agent transmission. The hypothesis is that tick saliva proteins critical to feeding success and pathogen infection of the host are injected into the host during the first 48 h of feeding and blocking their functions will protect animals against tick feeding and pathogen infection. This hypothesis is based on preliminary experimental evidence that repeated tick infestation of rabbits for 48 h with nymph or adult ticks conferred protective tick immunity as revealed by mortality failure of ticks to attach or remain attached onto host skin. Previous efforts to confer protective tick immunity by immunizing animals with single tick saliva recombinant proteins have produced mixed results. In this research we have proposed a previously unexplored approach, to immunize animals against tick feeding with multi-epitope chimeric tick saliva protein vaccine antigens. The idea is that immunity to these chimeric antigens will mimic protective tick immunity conferred tick saliva protein antigens during repeated infestations. There are 3 specific aims. The first is to clone cDNAs that encode A. americanum tick saliva proteins that are injected into the host during the first 48 h of tick feeding. The second is to validate immunogenicity of putative antigenic peptide regions in tick saliva proteins. Validated immunogenic peptides will represent tick saliva protein regions that mediate tick resistance in repeated tick feeding and will thus represent potential tick vaccine antigens. The third is to validate tick immunity and anamnestic antibody response of immunogenic peptide-cocktail immunized rabbits to tick infestation. The rationale is that if immunization of rabbits with immunogenic peptide-cocktails confers tick immunity that is comparable to that in repeated tick infestation, data from this application will set the foundation to design chimeric tick saliva proteins. 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（由申请方提供）：在美国，报告的人类病媒传播疾病主要是蜱媒传播。为了使蜱传疾病病原体在自然界中持续循环，需要成功喂养蜱。调节早期蜱虫摄食的分子机制还不清楚。它们对于理解蜱虫对病原体的获取和传播至关重要，而这反过来又将对设计控制蜱虫和蜱媒疾病的新方法至关重要。本提案的目标是对美洲钝眼蜱蜱唾液蛋白进行分子鉴定和靶向验证，这些蛋白在蜱进食的前48小时内被注射到宿主体内。关注该时间点的基本原理是，它先于蜱虫喂食、血餐摄入和蜱虫传播疾病病原体传播的关键方面。假设是，蜱唾液蛋白质的关键喂养成功和病原体感染的主机被注入到主机在第一个48小时的喂养和阻断其功能将保护动物对蜱喂养和病原体感染。这一假设是基于初步实验证据，反复蜱虫感染兔子48小时与若虫或成年蜱赋予保护性蜱免疫力所揭示的死亡率失败的蜱附着或保持附着到宿主皮肤上。以前的努力，赋予保护蜱免疫动物免疫与单蜱唾液重组蛋白产生了混合的结果。在这项研究中，我们提出了一个以前未探索的方法，免疫动物对蜱喂养与多表位嵌合蜱唾液蛋白疫苗抗原。这个想法是，对这些嵌合抗原的免疫力将模拟在重复感染期间赋予蜱唾液蛋白抗原的保护性蜱免疫力。有三个具体目标。第一步是克隆编码A.美洲蜱的唾液蛋白，在蜱进食的前48小时期间注射到宿主体内。第二是验证蜱唾液蛋白中推定的抗原肽区域的免疫原性。经验证的免疫原性肽将代表在反复蜱喂食中介导蜱抗性的蜱唾液蛋白区域，因此将代表潜在的蜱疫苗抗原。三是验证抗原肽混合物免疫家兔的蜱免疫力和回忆性抗体应答。基本原理是，如果用免疫原性肽-鸡尾酒免疫兔赋予与重复蜱侵染相当的蜱免疫力，则来自该应用的数据将为设计嵌合蜱唾液蛋白奠定基础。公共卫生相关性：在美国，蜱虫传播的媒介传播疾病比任何其他媒介节肢动物都多。与当前基于杀螨剂的蜱虫控制策略相关的限制威胁到蜱虫传播疾病遏制计划的未来可持续性，因此需要开发替代蜱虫控制策略。在开发替代蜱控制方法之前，鉴定调节蜱生理学和促进蜱进食的重要蜱蛋白是重要的。