Vector and Host Contributions to the Regulation of E. Chaffeensis Gene Expression

项目概要： 由埃立克体属的无形体科病原体引起的立克次体病和 无形体仍然是一个日益增长的公共卫生问题超过三十年，也是第二个 在美国和世界许多地方，蜱传播的人类感染的主要原因。尽管 节肢动物和脊椎动物的复杂细胞环境具有复杂的防御系统， 无形体科病原体进化出逃避宿主清除的策略。我们之前的研究 证明了脊椎动物和蜱细胞中的差异表达改变了宿主反应， 脊椎动物宿主清除/持久性的变化。我们竞争的核心假设 更新申请仍然是E. chaffeensis差异调节其基因表达， 宿主细胞的环境信号和宿主细胞特异性的基因表达是必不可少的 病原体在脊椎动物和蜱细胞环境中的持续生存。我们已经做出了实质性的 在实现上一个资助项目的三个具体目标方面取得的进展。从第一阶段到第二阶段 上一个供资周期包括许多同行审查的出版物，这为更多的出版物铺平了道路。 令人兴奋的新方向，这一拟议的竞争更新应用程序。三个新的目标 这一更新申请的具体目标有一个强有力的前提，得到了已发表研究的支持 结果和其他未公布的初步数据。使用该方法生成的大量新数据 以前的R 01赠款支持为以下三个具体目标奠定了坚实的基础 这一更新申请。1)鉴定E. chaffeensis影响RNA聚合酶功能，以支持了解病原体的宿主- 特异性差异基因表达。2)鉴定基因的功能意义， 对E. chaffeensis体内生长。3)突变和体内筛选在确定基因组 脊椎动物和蜱宿主中细菌致病的关键区域。拟议的具体目标 这是我们在上一个供资周期取得的实质性进展的合理延伸。 项目目标有很强的科学前提，因为它们得到了研究数据的支持 在许多同行评审的出版物中报告，并包括额外的初步数据。

PROJECT SUMMARY: Rickettsial diseases caused by the Anaplasmataceae family pathogens of the genera Ehrlichia and Anaplasma remain a growing public health concern for over three decades and are also the second leading cause of tick- borne human infections in the USA and many parts of the world. Despite the complex cellular environments of arthropods and vertebrates having sophisticated systems of defense, the Anaplasmataceae pathogens evolved strategies to evade host clearance. Our prior studies demonstrated that the differential expression in vertebrate and tick cells alters host responses leading to variations in vertebrate host clearance/persistence. The central hypothesis of our competing renewal application remains that E. chaffeensis differentially regulates its gene expression in response to host cell environmental signals and that the host cell-specific gene expression is essential for pathogen’s continued survival in vertebrate and tick cell environments. We have made substantial progress in addressing the three specific aims of the previous funded project. The progress from the prior funded cycle included numerous peer-reviewed publications, which paved the way for additional exciting new directions for this proposed competing renewal application. Goals set for the three new specific aims of this renewal application have a strong premise, as supported with published research results and with additional unpublished preliminary data. The extensive novel data generated with the previous R01 grant support formed a strong foundation for the following proposed three specific aims of this renewal application. 1) Characterize sequence-specific DNA binding proteins (DBPs) in E. chaffeensis impacting RNA polymerase function in support of understanding the pathogen’s host- specific differential gene expression. 2) Characterize the functional significance of genes identified as essential for E. chaffeensis in vivo growth. 3) Mutagenesis and in vivo screening in defining genomic regions critical for the bacterial pathogenesis in vertebrate and tick hosts. The proposed specific aims are a logical extension of the substantial progress we have made during the previous funding cycle. The project goals have a strong scientific premise, as they are supported with the research data reported in many peer-reviewed publications and with the inclusion of additional preliminary data.