MOLECULAR MECHANISMS OF MSP2 VARIATION IN RICKETTSIAE

描述（改编自申请人的摘要）： 这一建议是为了提高我们对发病机制的理解， 人类埃立克体病和相关蜱传立克次体病原体 和动物这些病原体包括由以下病原体引起的人类埃立克体感染： 查菲埃立克体与人粒细胞白血病病原体 埃立克体病以及E. canis、犬棘球绦虫E.马、反刍牛疫霉和无形体 动物的边缘感染。感染的一个共同特征是 这些立克次体病原体是它们在人和/或动物中持续存在的能力， 宿主并导致长期感染。动物长期感染 储存宿主有效地维持环境中的病原体， 确保蜱虫媒介向前传播。最近人们认识到， 这些立克次体在分子水平上也有一些共同的特征。他们 合成类似的主要外膜蛋白（MSP 2同系物）， 被感染的人和动物的血清强烈识别， 由多基因家族编码。MSP 2同源物已被提议作为诊断性的 这些立克次体物种中的几种中的抗原，并且已知至少 部分保护性抗原对抗肝攻击感染 立克次体然而，MSP 2同源物的序列变异可能限制MSP 2的使用。 这些抗原用于诊断或疫苗接种，并可能是一个长期的因素， 立克次体的持续存在。MSP 2最初在A.边缘和 牛感染这种立克次体提供了一个极好的模型， 分析了持续性的机制和序列变异的影响， MSP 2.在这个建议中，基因序列变异的分子机制， 将定义编码MSP 2（msp 2）的转录物。具体目标是：1） 确定无形体中msp 2基因RNA转录物的完整结构 确定msp 2基因的可变区和保守区 在急性和持续感染A.边缘; 3） 表征急性和慢性炎症中来自msp 2基因转录物的蛋白质表达， 持续感染A. 4）确定边缘的基因组机制， msp 2变异在A. 5）比较A. 在人粒细胞埃里希体病的病原体中。本研究 将为比较涉及MSP 2的致病机制提供基础 这些立克次体的变异，特别是密切相关的立克次体 引起无形体病和人粒细胞埃里希体病。

DESCRIPTION (Adapted from the Applicant's Abstract): The long term objective of this proposal is to improve our understanding of the mechanisms of pathogenesis of ehrlichial diseases and related tick-borne rickettsial pathogens of humans and animals. These pathogens include ehrlichial infections of humans caused by Ehrlichia chaffeensis and the causative agent of human granulocytic ehrlichiosis as well as E. canis, E. equi, Cowdria ruminantium and Anaplasma marginale infections of animals. A common feature of infections caused by these rickettsial pathogens is their ability to persist in human and/or animal reservoir hosts and cause long-term infection. Long-term infections of animal reservoir hosts effectively maintain the pathogens in the environment and ensure onward transmission by the tick vector. It has been recognized recently that these rickettsiae also share several features at the molecular level. They synthesize similar major outer membrane proteins (MSP2 homologs) that are strongly recognized by sera from infected humans and animals and that can be encoded by multigene families. MSP2 homologs have been proposed as diagnostic antigens in several of these rickettsial species and are known to be at least partially protective antigens against challenge infection with live rickettsiae. However, sequence variation of MSP2 homologs may limit use of these antigens for diagnosis or vaccination and may be a factor in long term persistence of the rickettsiae. MSP2 was initially defined in A. marginale and infections of cattle with this rickettsia provide an excellent model for analyzing mechanisms of persistence and the influence of sequence variation in MSP2. In this proposal, the molecular mechanisms of sequence variation in gene transcripts encoding MSP2 (msp2) will be defined. The specific aims are: 1) Define the complete structure of an msp2 gene RNA transcript in Anaplasma marginale; 2) Determine variable and conserved regions of msp2 gene transcripts in acute and persistent infections with A. marginale; 3) Characterize protein expression from msp2 gene transcripts in acute and persistent infections with A. marginale; 4) Determine the genomic mechanisms of msp2 variation in A. marginale; 5) Compare msp2 RNA transcripts in A. marginale and in the agent of human granulocytic ehrlichiosis. This study will provide a basis for comparison of pathogenic mechanisms involving MSP2 variation in these rickettsiae, particularly in the closely related rickettsiae causing anaplasmosis and human granulocytic ehrlichiosis.