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）是人类上呼吸道的常见定植菌， 它的定植可导致鼻窦炎、肺炎、中耳炎、脑膜炎和/或败血症。肺炎球菌 全球每年有超过一百万人因感染而死亡。最近的工作表明，一个关键宿主 针对肺炎球菌和其他呼吸道病原体（例如分枝杆菌）的防御机制 结核病涉及在感染部位使用充满锌的吞噬细胞，从而用锌毒害这些生物体。 这些细菌暴露于过量的锌浓度中会导致中毒，因为 锰依赖性酶的错金属化。为了避免锌中毒，肺炎球菌必须迅速做出反应 环境中这种过渡金属的水平发生变化。小调节 RNA (sRNA) 具有关键作用 通过共转录或转录后调节基因表达，在介导对应激的快速反应中发挥作用。 然而，关于 sRNA 如何促进肺炎链球菌生理学的公开信息很少 和毒力。该提案的总体目标是了解 Ccn sRNA 如何控制 S. 肺炎链球菌锌稳态。该项目基于初步数据，表明 Ccn sRNA 是 对于鼻咽内浓度的肺炎链球菌毒力和对锌的抵抗力很重要 以及感染期间宿主的血液。该提议的中心假设是 Ccn sRNA 介导 肺炎链球菌对过量锌的快速、适应性反应。在目标 1 中，Ccn sRNA 的调节功能 将确定存在或不存在锌胁迫下的基因表达。在目标 2 中，该机制通过 将阐明 Ccn sRNA 预防锌中毒的机制。本研究的意义在于 它的完成将导致人们更好地了解 sRNA 介导的基因调控和机制 肺炎链球菌和其他革兰氏阳性菌中的锌应激反应。此项研究具有创新性， 因为 (1) 将利用新方法来识别肺炎链球菌 sRNA 的靶标，(2) 拟议的 这项工作将首次确定 sRNA 在提供另一层 Zn 控制方面的功能 稳态，以及（3）这些研究应该揭示新发现的转运蛋白在维持 Zn 方面的作用 水平。