Small RNA based control of zinc homeostasis in Streptococcus pneumoniae

肺炎链球菌(简称肺炎球菌)是人类上呼吸道常见的定殖菌， 其定植可导致鼻窦炎、肺炎、中耳炎、脑膜炎和/或败血症。肺炎双球菌 全世界每年有100多万人死于感染。最近的研究表明，一个关键的主机 对肺炎球菌和其他呼吸道病原体如分枝杆菌的防御机制 结核病涉及到感染部位使用富含锌的吞噬细胞，这些吞噬细胞用锌毒害这些生物。 这些细菌暴露在过量的锌浓度下会导致中毒，其结果是 依赖于锰的酶的非金属化。为了避免锌中毒，肺炎球菌必须迅速对 这种过渡金属在其环境中的水平变化。小的调控RNA(SRNA)具有关键作用 通过协同或转录后调节基因表达，在调节对应激的快速反应中发挥作用。 然而，关于srna如何对肺炎链球菌的生理学起作用的已发表的信息很少。 和致命性。这项提案的总体目标是了解CCN sRNAs如何控制S. 肺炎支气管炎锌稳态。该项目基于初步数据，显示CCN sRNA是 对肺炎链球菌的毒力和对鼻咽内锌浓度的抵抗力很重要 以及感染期间宿主的血液。这一提议的中心假设是CCN sRNA介导了 肺炎链球菌对过量锌的快速适应性反应。在目标1中，CCN sRNAs在调节 在锌胁迫存在或不存在的情况下，基因表达将被确定。在目标2中，该机制通过 哪些CCN sRNAs可以防止锌中毒将被阐明。拟议研究的意义在于 它的完成将使我们更好地理解sRNA介导的基因调控和 肺炎链球菌和其他革兰氏阳性菌的锌应激反应。这项拟议的研究是创新的， 因为(1)将利用新的方法来识别肺炎链球菌sRNAs的靶标，(2)建议的 这项工作将首次确定sRNA在提供锌的另一层控制方面的功能 动态平衡，以及(3)这些研究应该揭示一种新发现的转运蛋白在维持锌含量方面的作用 级别。

Streptococcus pneumoniae (pneumococcus) is a common colonizer of the human upper respiratory tract, and its colonization can lead to sinusitis, pneumonia, otitis media, meningitis, and/or septicemia. Pneumococcal infections result in over one million deaths per year worldwide. Recent work has shown that that a key host defense mechanism against pneumococcus and other respiratory pathogens such as Mycobacterium tuberculosis involves employing to infection sites Zn laden phagocytes, which poison these organisms with Zn. Exposure of these bacteria to excessive Zn concentrations causes intoxication as a consequence of mismetallation of Mn-dependent enzymes. To avoid Zn poisoning, pneumococcus must rapidly respond to changes in the levels of this transition metal in its environment. Small regulatory RNAs (sRNAs) have a pivotal role in mediating, rapid responses to stresses by co- or post-transcriptionally regulating gene expression. However, there is little published information regarding how sRNAs contribute to S. pneumoniae physiology and virulence. The overall objective of this proposal is to understand how the Ccn sRNAs control S. pneumoniae Zn homeostasis. This project is based upon preliminary data showing that the Ccn sRNAs are important for S. pneumoniae virulence and resistance to Zn at concentrations found within the nasopharynx and blood of its host during infection. The central hypothesis for this proposal is that Ccn sRNAs mediate the rapid, adaptive response of S. pneumoniae to excess Zn. In Aim 1, the function of the Ccn sRNAs in regulating gene expression in the presence or absence of Zn stress will be established. In Aim 2, the mechanism by which the Ccn sRNAs prevent Zn intoxication will be elucidated. The significance of the proposed research is that its completion will result in a greater understanding of sRNA-mediated gene regulation and mechanisms of Zn stress response in S. pneumoniae and other Gram-positive bacteria. This proposed research is innovative, because (1) novel approaches will be utilized to identify the targets of S. pneumoniae sRNAs, (2) the proposed work will establish for the first time the function of sRNAs in providing another layer of control of Zn homeostasis, and (3) these studies should reveal the role of a newly identified transporter in maintaining Zn levels.