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

项目总结： 埃利希菌属无浆体科病原体引起的立克次体病 三十多年来，无浆体仍然是一个日益严重的公共卫生问题，也是第二个 在美国和世界上许多地区，硬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， 无浆体科病原菌进化出逃避寄主清除的策略。我们之前的研究 证明了脊椎动物和扁虱细胞的差异表达改变了宿主的反应 脊椎动物宿主清除/持久性的变化。我们竞争的核心假设是 更新应用仍然是查菲乳杆菌对其基因表达的差异性调控 宿主细胞环境信号，宿主细胞特有的基因表达对 病原体在脊椎动物和壁虱细胞环境中的持续生存。我们已经取得了实质性的进展 在实现先前资助项目的三个具体目标方面取得了进展。来自美国的进展 上一个资助周期包括许多同行评议的出版物，这为更多 令人振奋的新方向，为这项拟议的竞争续签申请。为三个新项目设定目标 此次续签申请的具体目标有一个强有力的前提，这一点得到了已发表的研究的支持 结果和其他未公布的初步数据。生成的大量新奇数据 以前的R01赠款支持为以下提议的三个具体目标奠定了坚实的基础 这份续签申请的。1)鉴定了E。 影响RNA聚合酶功能的查菲斯支持了解病原体的寄主- 特异性差异基因表达。2)确定以下基因的功能意义 是查菲乳杆菌体内生长所必需的。3)定义基因组的诱变和活体筛选 脊椎动物和壁虱宿主中细菌致病的关键区域。拟议的具体目标 是我们在上一个供资周期取得的实质性进展的合乎逻辑的延伸。 项目目标有很强的科学前提，因为它们有研究数据支持 在许多同行评议的出版物中进行了报告，并纳入了额外的初步数据。

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of this renewal application have a strong premise, as supported with published research results and with additional unpublished preliminary data.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.