MOLECULAR MECHANISMS OF MSP2 VARIATION IN RICKETTSIAE

描述(改编自申请人的摘要)：长期目标 这一建议是为了提高我们对发病机制的理解。 人类埃立克次体疾病和相关硬蜱传播的立克次体病原体 还有动物。这些病原体包括由以下原因引起的人类埃利希氏菌感染 查菲埃立克体与人类粒细胞病原体 埃立克体病以及犬埃希氏菌、马埃希氏菌、反刍柯氏杆菌和无浆体 动物的边缘感染。由以下原因引起的感染的一个共同特征 这些立克次体病原体是指它们在人类和/或动物体内持续存在的能力 水库是宿主，并导致长期感染。动物的长期感染 水库宿主有效地保持了环境中的病原体和 确保通过扁虱传播媒介继续传播。它最近已经被认识到了 这些立克次体在分子水平上也有几个共同的特征。他们 合成类似的主要外膜蛋白(MSP2同源物)，它们是 被感染的人和动物的血清强烈识别，这可能是 由多基因家族编码。MSP2同源基因已被提出用于诊断 在这些立克次体物种中的几种抗原，已知至少是 抗活体攻击感染的部分保护性抗原 立克次体。然而，MSP2同系物的序列变异可能限制其使用 这些抗原用于诊断或接种疫苗，从长远来看可能是一个因素 立克次体的持久性。MSP2最初是在A.Margale和 感染这种立克次体的牛提供了一个很好的模型 持续时间的机制分析及序列变异的影响 MSP2.在这一建议中，基因序列变异的分子机制 将定义编码MSP2(MSP2)的抄本。具体目标是：1) 在无浆体中确定msp2基因RNA转录本的完整结构 2)确定msp2基因的可变区和保守区 边缘念珠菌急性和持续性感染的转录本；3) 急性和慢性粒细胞白血病msp2基因转录本的蛋白表达特征 边际曲霉的持续感染；4)确定了 Msp2在边际拟青霉中的变异；5)比较拟青霉msp2RNA转录本。 边缘和人类粒细胞性埃立克体病的病原体。本研究 将为比较涉及MSP2的致病机制提供基础 这些立克次体的变异，特别是在密切相关的立克次体中 导致无浆体病和人类粒细胞性埃立克体病。

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.