Global Regulation of Gene expression in Streptococcus pneumoniae

描述（由申请人提供）：肺炎链球菌通常是人类鼻咽部的居民，随着环境变化而变得致病性。作为一种病原体，它会扩散到肺部（肺炎）、中枢神经系统（脑膜炎）和中耳（中耳炎）。肺炎链球菌引起的死亡率和发病率主要见于幼儿和老年人。信号转导在感知肺炎链球菌的生存环境和决定其是否具有致病性方面起着重要作用。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。拟议的研究将集中于反应调节因子RitR，丝氨酸/苏氨酸激酶磷酸酶对及其相互作用。缺乏RitR的肺炎球菌无法感染肺部，这使得该蛋白成为与抗菌化疗开发相关的有吸引力的研究目标。丝氨酸/苏氨酸激酶和磷酸酶对肺炎链球菌的毒力也是必需的。我们的工作假设是：(1)RitR缺乏同源His激酶，但与丝氨酸/苏氨酸激酶磷酸酶系统相互作用；(2) RitR是肺炎链球菌中抑制Piu血红素转运蛋白合成的全局调控蛋白；(3)Ser/Thr激酶和磷酸酶是Piu血红素转运蛋白表达所必需的。本提案的具体目的是：(1)表征肺炎链球菌中存在的RitR，丝氨酸/苏氨酸激酶和丝氨酸/苏氨酸磷酸酶之间的新型相互作用，(2)研究这些蛋白如何调节Piu血红素转运蛋白的表达，以及(3)鉴定由RitR/Stp/Stk复合物调节的其他基因。公共卫生相关性：肺炎链球菌通常是人类鼻咽部的居民，随着环境变化而变得致病性。作为一种病原体，它会扩散到肺部（肺炎）、中枢神经系统（脑膜炎）和中耳（中耳炎）。肺炎链球菌引起的死亡率和发病率主要见于幼儿和老年人。信号转导在感知肺炎链球菌的生存环境和决定其是否具有致病性方面起着重要作用。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。拟议的研究将集中于反应调节因子RitR，丝氨酸/苏氨酸激酶磷酸酶对及其相互作用。缺乏RitR的肺炎球菌无法感染肺部，这使得该蛋白成为与抗菌化疗开发相关的有吸引力的研究目标。丝氨酸/苏氨酸激酶和磷酸酶对肺炎链球菌的毒力也是必需的。我们的工作假设是：(1)RitR缺乏同源His激酶，但与丝氨酸/苏氨酸激酶磷酸酶系统相互作用；(2) RitR是肺炎链球菌中抑制Piu血红素转运蛋白合成的全局调控蛋白；(3)Ser/Thr激酶和磷酸酶是Piu血红素转运蛋白表达所必需的。本提案的具体目的是：(1)表征肺炎链球菌中存在的RitR，丝氨酸/苏氨酸激酶和丝氨酸/苏氨酸磷酸酶之间的新型相互作用，(2)研究这些蛋白如何调节Piu血红素转运蛋白的表达，以及(3)鉴定由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.