Mechanisms of Developmental Regulation in Chlamydia

项目总结/摘要 衣原体是公共卫生领域最重要的传染源之一， perspective.向卫生部报告的衣原体感染病例超过150万例， 疾病控制和预防中心每年，使其成为美国最常见的传染病。 衣原体引起一种不寻常的细胞内感染， 在细菌的两种发育形式之间：基本体（EB）， 感染性但休眠的形式，和网状体（RB），这是细胞内， 复制形式。基因表达仅限于RB，而EB中的转录沉默 已归因于两种组蛋白样蛋白HctA和HctB的DNA缩合。 我们假设第二种沉默机制，其中EB中的RNA聚合酶是 以可逆方式抑制，由3型分泌（T3 S）活性控制。在 目的1我们将研究T3 S伴侣Scc 4如何与其他两种T3 S蛋白一起， 协同调节RNA聚合酶活性和T3 S分泌活性。在目标2中， 将研究第二个T3 S伴侣Scc 2，我们建议作为T3 S调节的 衣原体转录沉默子。在目标3中，我们将研究组蛋白样蛋白， 确定它们是否均匀地或以启动子特异性方式沉默转录。这些 研究将定义EB中转录沉默的机制，这是一个核心的 细胞内衣原体感染的发育基因调控特点及临床意义 潜在的治疗靶点。

Project Summary/Abstract Chlamydia is one of the most important infectious agents from a public health perspective. More than 1.5 million cases of chlamydial infections are reported to the CDC annually, making it the most commonly reported infectious disease in the U.S. Chlamydia causes an unusual intracellular infection in which there is conversion between two developmental forms of the bacterium: the elementary body (EB), which is the infectious but dormant form, and the reticulate body (RB), which is the intracellular, replicating form. Gene expression is limited to RBs, and transcriptional silencing in EBs has been attributed to DNA condensation by two histone-like proteins, HctA and HctB. We hypothesize a second silencing mechanism in which RNA polymerase in EBs is inhibited in a reversible manner that is controlled by Type 3 secretion (T3S) activity. In Aim 1 we will study how a T3S chaperone Scc4, together with two other T3S proteins, coordinately regulates RNA polymerase activity and T3S secretion activity. In Aim 2, we will investigate a second T3S chaperone Scc2 that we propose as a T3S-regulated silencer of chlamydial transcription. In Aim 3, we will study the histone-like proteins to determine if they silence transcription uniformly or in a promoter-specific manner. These studies will define the mechanisms of transcriptional silencing in EBs, which is a central feature of developmental gene regulation in the intracellular Chlamydia infection and a potential therapeutic target.