Inter-kingdom signaling by A. actinomycetemcomitans

描述（由申请人提供）：牙周炎是一种广泛且昂贵的疾病，主要表现在口腔中，但也与全身性疾病如动脉粥样硬化和类风湿性关节炎有关。 尽管有几种生物 鉴定为牙周致病菌，A.伴随放线菌与侵袭性牙周炎密切相关。 我们先前的工作表明，群体感应是必不可少的A。 放线菌共生菌的毒力和我们确定的QseBC两个组件系统作为一个关键组成部分的群体感应途径。 我们的新结果表明，QseBC可能与宿主产生的儿茶酚胺激素相互作用，因此，QseBC可能介导细胞密度依赖性信号传导和界间信号传导。 本研究旨在探讨这一双组分系统与儿茶酚胺类激素的相互作用机制，并探讨其在调节铁吸收中的潜在作用。伴放线菌 目标1将确定是否儿茶酚胺激素和铁代表激活QseBC的信号，并确定结合所需的QseC传感器的功能基序。 还将使用基因组微阵列鉴定在QseBC活化后调节的基因。 目的2将研究一个操纵子编码一个假定的肠杆菌素受体和转运蛋白，并确定该受体是否与儿茶酚胺铁复合物相互作用。 肠杆菌素受体对毒力的贡献也将使用牙周炎的小鼠模型进行检查。 我们还表明，QseBC可以耦合到细胞应激反应，通过两个铁响应毒素-抗毒素（TA）系统的活动。将在目的3中研究该调节网络，以确定在铁限制条件下是否诱导应激蛋白酶的表达，以及这些蛋白酶是否通过降解不稳定的抗毒素来激活TA毒素。 研究了TA毒素激活对A.放线菌共生菌也将被确定。 本研究的总体目标是更好地了解激活关键QseBC双组分系统的功能结果以及通过QseBC的信号传导如何有助于毒力。

DESCRIPTION (provided by applicant): Periodontitis is a widespread and costly disease that is primarily manifest in the oral cavity but is also associated with systemic dieases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens, A. actinomycetemcomitans has been strongly associated with aggressive forms of periodontitis. Our prior work showed that quorum sensing is essential for A. actinomycetemcomitans virulence and we identified the QseBC two component system as a critical component of the quorum sensing pathway. Our new results suggest that QseBC may interact with catecholamine hormones produced by the host and thus, QseBC may mediate both cell density dependent signaling and inter-kingdom signaling. This application focuses on the mechanisms of interaction of the two component system with catecholamine hormones and is potential role in regulating iron uptake by A. actinomycetemcomitans. Aim 1 will determine if catecholamine hormones and iron represent signals that activate QseBC and identify functional motifs of the QseC sensor that are required for binding. The genes that are regulated upon activation of QseBC will also be identifed using genomic microarrays. Aim 2 will study an operon encoding a putative enterobactin receptor and transporter and determine if this receptor interacts with catecholamine-iron complexes. The contribution of the enterobactin receptor to virulence will also be examined using a mouse model of periodontitis. We have also shown that QseBC may be coupled to the cell stress response through the activity of two iron responsive toxin-antitoxin (TA) systems. This regulatory network will be studied in Aim 3 to determine if the expression of stress proteases is induced under iron limiting conditions and whether these proteases activate the TA toxins by degrading the labile antitoxin. The effect of TA toxin activation on the expression of QseBC and virulence of A. actinomycetemcomitans will also be determined. The overall goal of this study is to better understand the functional outcomes of activation of the essential QseBC two component system and how signaling through QseBC contributes to virulence.