Global Regulation of Gene expression in Streptococcus pneumoniae

描述（由申请人提供）：肺炎链球菌通常作为人类鼻咽部的居民发现，其响应于环境变化而变得致病。作为病原体，它传播到肺部（肺炎），中枢神经系统（脑膜炎）和中耳（中耳炎）。死亡率和发病率由于S。肺炎主要见于非常年轻和老年人。信号转导在S.肺炎，并决定成为致病性。我们的长期目标是通过信号转导研究全局基因调控，特别是了解信号转导途径激活后发生的细胞内事件。拟议的研究将集中在反应调节RitR，丝氨酸/苏氨酸激酶磷酸酶对，以及它们之间的相互作用。缺乏RitR的肺炎球菌不能感染肺部，这使得这种蛋白质成为与抗微生物化疗的发展有关的有吸引力的研究目标。丝氨酸/苏氨酸激酶和磷酸酶也是S.肺炎。我们的工作假设是：（1）RitR缺乏同源His激酶，但与Ser/Thr激酶磷酸酶系统相互作用;（2）RitR是S. pneumoniae的丝氨酸/苏氨酸激酶和磷酸酶抑制Piu血红素转运蛋白的合成，以及（3）Ser/Thr激酶和磷酸酶是Piu血红素转运蛋白表达所必需的。本研究的主要目的是：（1）研究丝氨酸/苏氨酸激酶RitR与丝氨酸/苏氨酸磷酸酶之间的相互作用。肺炎，（2）检查这些蛋白质如何调节Piu血红素转运蛋白的表达，以及（3）鉴定受RitR/Stp/Stk复合物调节的其他基因。 公共卫生相关性：肺炎链球菌通常被发现作为人类鼻咽的居民，其响应于环境变化而变得致病。作为病原体，它传播到肺部（肺炎），中枢神经系统（脑膜炎）和中耳（中耳炎）。死亡率和发病率由于S。肺炎主要见于非常年轻和老年人。信号转导在S.肺炎，并决定成为致病性。我们的长期目标是通过信号转导研究全局基因调控，特别是了解信号转导途径激活后发生的细胞内事件。拟议的研究将集中在反应调节RitR，丝氨酸/苏氨酸激酶磷酸酶对，以及它们之间的相互作用。缺乏RitR的肺炎球菌不能感染肺部，这使得这种蛋白质成为与抗微生物化疗的发展有关的有吸引力的研究目标。丝氨酸/苏氨酸激酶和磷酸酶也是S.肺炎。我们的工作假设是：（1）RitR缺乏同源His激酶，但与Ser/Thr激酶磷酸酶系统相互作用;（2）RitR是S. pneumoniae的丝氨酸/苏氨酸激酶和磷酸酶抑制Piu血红素转运蛋白的合成，以及（3）Ser/Thr激酶和磷酸酶是Piu血红素转运蛋白表达所必需的。本研究的主要目的是：（1）研究丝氨酸/苏氨酸激酶RitR与丝氨酸/苏氨酸磷酸酶之间的相互作用。肺炎，（2）检查这些蛋白质如何调节Piu血红素转运蛋白的表达，以及（3）鉴定受RitR/Stp/Stk复合物调节的其他基因。

DESCRIPTION (provided by applicant): Streptococcus pneumoniae is normally found as an inhabitant of the human nasopharynx that becomes pathogenic in response to environmental changes. As a pathogen, it spreads to the lungs (pneumonia), the central nervous system (meningitis), and the middle ear (otitis media). Mortality and morbidity due to S. pneumoniae is seen primarily in the very young and elderly. Signal transduction plays a major role in sensing the environment of S. pneumoniae and in its decision to become pathogenic. Our long-term goal is to study global gene regulation by signal transduction, particularly to learn about the intracellular events that occur following activation of signal transduction pathways. The proposed studies will focus on the response regulator RitR, on a Serine/Threonine kinase phosphatase pair, and on their mutual interactions. Pneumococci that lack RitR are unable to infect the lung, which makes this protein an attractive target to study in connection with the development of antimicrobial chemotherapy. Serine/Threonine kinases and phosphatases are also necessary for virulence in S. pneumoniae. It is our working hypothesis that: (1) RitR lacks a cognate His kinase, but interacts with a Ser/Thr kinase phosphatase system; (2) RitR is a global regulatory protein in S. pneumoniae which represses the synthesis of the Piu heme transporter, and (3) Ser/Thr kinase and phosphatase are required for Piu heme transporter expression. The specific aims of this proposal are: (1) To characterize the novel interaction between RitR, a Ser/Thr Kinase, and Ser/Thr phosphatase present in S. pneumoniae, (2) To examine how these proteins regulate expression of the Piu heme transporter, and (3) To identify other genes regulated by the RitR/Stp/Stk complex. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae is normally found as an inhabitant of the human nasopharynx that becomes pathogenic in response to environmental changes. As a pathogen, it spreads to the lungs (pneumonia), the central nervous system (meningitis), and the middle ear (otitis media). Mortality and morbidity due to S. pneumoniae is seen primarily in the very young and elderly. Signal transduction plays a major role in sensing the environment of S. pneumoniae and in its decision to become pathogenic. Our long-term goal is to study global gene regulation by signal transduction, particularly to learn about the intracellular events that occur following activation of signal transduction pathways. The proposed studies will focus on the response regulator RitR, on a Serine/Threonine kinase phosphatase pair, and on their mutual interactions. Pneumococci that lack RitR are unable to infect the lung, which makes this protein an attractive target to study in connection with the development of antimicrobial chemotherapy. Serine/Threonine kinases and phosphatases are also necessary for virulence in S. pneumoniae. It is our working hypothesis that: (1) RitR lacks a cognate His kinase, but interacts with a Ser/Thr kinase phosphatase system; (2) RitR is a global regulatory protein in S. pneumoniae which represses the synthesis of the Piu heme transporter, and (3) Ser/Thr kinase and phosphatase are required for Piu heme transporter expression. The specific aims of this proposal are: (1) To characterize the novel interaction between RitR, a Ser/Thr Kinase, and Ser/Thr phosphatase present in S. pneumoniae, (2) To examine how these proteins regulate expression of the Piu heme transporter, and (3) To identify other genes regulated by the RitR/Stp/Stk complex.