Small RNA based control of zinc homeostasis in Streptococcus pneumoniae

基于小RNA的肺炎链球菌锌稳态控制

• 批准号: 10625448
• 负责人: Nicholas R. De Lay
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625448
• 关键词: Bacteria; Bacterial Infections; Base Pairing; Binding Sites; Bioinformatics; Biological Assay; Blood; Buffers; Carrier Proteins; Cells; Cellular Morphology; Cessation of life; Complement; Data; Defect; Disease; Ectopic Expression; Environment; Enzymes; Exposure to; Gene Expression; Gene Expression Regulation; Genes; Genome; Glutathione; Glutathione Reductase; Gram-Positive Bacteria; Growth; Homeostasis; Host Defense Mechanism; Human; Impairment; In Vitro; Infection; Intoxication; Invaded; Knowledge; Mediating; Meningitis; Messenger RNA; Metabolic; Metals; Methods; Molecular Chaperones; Morphology; Mycobacterium tuberculosis; Nasopharynx; Nutritional Immunity; Organism; Otitis Media; Pathway interactions; Phagocytes; Physiology; Pneumococcal Infections; Pneumonia; Poison; Poisoning; Post-Transcriptional Regulation; Process; Proteins; Publishing; RNA; RNA purification; Research; Resistance; Reverse Transcription; Ribosomes; Role; Septicemia; Sinusitis; Site; Small RNA; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Stress; System; Testing; Time; Toxic effect; Transcript; Transition Elements; Upper respiratory tract; Virulence; Work; Zinc; access restrictions; aptamer; biological adaptation to stress; digital; experience; glutathione transporter; human pathogen; innovation; mutant; novel; novel strategies; opportunistic pathogen; pathogen; pathogenic bacteria; posttranscriptional; prevent; respiratory pathogen; response; targeted treatment; transcriptome sequencing

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.

肺炎链球菌（肺炎球菌）是人上呼吸道的常见菌落， 它的定殖可能导致鼻窦炎，肺炎，中耳炎，脑膜炎和/或败血病。肺炎球菌 感染导致全球每年超过100万人死亡。最近的工作表明这是关键主机 防御机制针对肺炎球菌和其他呼吸道病原体，例如分枝杆菌 结核病涉及使用Zn Laden吞噬细胞的感染部位，这些吞噬细胞用Zn毒害这些生物。 这些细菌暴露于过度的Zn浓度会导致中毒 MN依赖性酶的不易裂。为避免锌中毒，肺炎球菌必须迅速做出反应 这种过渡金属在其环境中的水平变化。小监管RNA（SRNA）具有关键 在介导，通过转录后调节基因表达的介导，快速反应应力。 但是，几乎没有关于SRNA如何对肺炎链球菌生理贡献的信息 和毒力。该提案的总体目的是了解CCN SRNAS控制。 肺炎锌稳态。该项目基于初步数据，表明CCN SRNA是 在鼻咽内发现的肺炎链球菌毒力和对Zn的抗性很重要 和宿主的血液在感染期间。该提议的中心假设是CCN SRNA介导 肺炎链球菌对多余的锌的快速自适应反应。在AIM 1中，CCN SRNA在调节中的功能 在存在或不存在锌应激的情况下，基因表达将建立。在AIM 2中，该机制通过 CCN SRNA可防止锌中毒。拟议的研究的重要性是 它的完成将导致对SRNA介导的基因调节和机制有更深入的了解 肺炎链球菌和其他革兰氏阳性细菌的锌应力反应。这项拟议的研究是创新的， 因为（1）将使用新颖的方法来识别肺炎链球菌的靶标，（2）提议 工作将首次建立SRNA的功能，以提供Zn的另一层控制层 稳态，（3）这些研究应揭示新鉴定的转运蛋白在维持锌中的作用 水平。