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者， 其定殖可导致鼻窦炎、肺炎、中耳炎、脑膜炎和/或败血症。肺炎球菌 感染每年在全世界造成超过一百万人死亡。最近的研究表明， 对肺炎球菌和其他呼吸道病原体如分枝杆菌的防御机制 结核病涉及在感染部位使用锌负载的吞噬细胞，其用锌毒害这些生物体。 这些细菌暴露于过量的锌浓度会导致中毒， 锰依赖酶的代谢异常。为了避免锌中毒，肺炎球菌必须迅速响应锌中毒。 这种过渡金属在其环境中的含量变化。小调节RNA（sRNAs）在细胞内具有关键的 通过共转录或转录后调节基因表达来介导对应激的快速反应。 然而，关于sRNA如何促进S.肺炎生理学 和毒性。本研究的总体目标是了解Ccn sRNA如何控制S. 锌稳态。该项目基于初步数据，表明Ccn sRNA是 重要的是S。在鼻咽内发现的浓度下， 和宿主的血液。该建议的中心假设是Ccn sRNAs介导了 S. pneumoniae感染过量Zn。在目的1中，Ccn sRNA在调节细胞凋亡中的功能被证实。 将建立在存在或不存在Zn胁迫下的基因表达。在目标2中， 将阐明Ccn sRNA预防锌中毒的机制。本研究的意义在于 它的完成将导致更好地了解sRNA介导的基因调控和机制， Zn胁迫对S.肺炎和其他革兰氏阳性菌。这项研究具有创新性， 因为（1）新的方法将被用于识别S.肺炎sRNAs，（2）提出的 这项工作将首次确定sRNA在提供另一层锌控制方面的功能， 稳态，（3）这些研究应该揭示一个新发现的转运蛋白在维持锌 程度.