Coordinate regulation of competence and pneumocin production in S. pneumoniae

肺炎链球菌能力和肺炎链球菌素产生的协调调节

• 批准号: 8500904
• 负责人: Suzanne Rachel Dawid
• 金额: $ 34.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500904
• 关键词: Address; Antibiotic Resistance; Antibiotics; Antibodies; Bacteria; Bacterial Meningitis; Binding; Cell Density; Cells; Competence; Cytolysis; DNA; DNA Sequence; Disease; Environmental Risk Factor; Event; Genes; Genetic; Genetic Materials; Genetic Recombination; Genetic Transcription; Genetic Variation; Genomics; Goals; Horizontal Gene Transfer; Human; Immunity; In Vitro; Integration Host Factors; Kinetics; Lytic; Measures; Mediating; Microbial Biofilms; Modeling; Mus; Nasopharynx; Nose; Organism; Otitis Media; Pathway interactions; Peptides; Pheromone; Play; Pneumonia; Population; Predatory Behavior; Prevention strategy; Production; Proteins; Regulation; Regulon; Relative (related person); Resistance; Role; Serine Protease; Source; Streptococcus; Streptococcus pneumoniae; Structure; Surface; System; Target Populations; Transcript; Up-Regulation; Vaccination; Vaccines; Virulent; bacteriocin; genetic regulatory protein; genetic resource; genome analysis; human morbidity; human mortality; in vivo; member; microbial; microbial community; pathogen; pressure; promoter; public health relevance; quorum sensing; resilience; response; tool; treatment strategy; uptake

DESCRIPTION (provided by applicant): Streptococcus pneumoniae (pneumococcus) is an important human pathogen and the most common cause of bacterial meningitis, pneumonia and otitis media. Although it can cause significant disease, pneumococcus is part of the normal nasopharyngeal flora. Its ability to take up and incorporate foreign DNA has allowed pneumococcus to resist attempts at clearance by providing a resource for genetic adaptation. Genome analysis has demonstrated that this species is characterized by an enormous amount of genetic diversity largely derived from recombination with DNA from other streptococci. The competence state in pneumococcus is regulated by a quorum sensing system controlled by the com system which drives the production of a large number of genes including those involved in DNA uptake and recombination. Competent pneumococci can lyse non-competent members of the population releasing their DNA via a mechanism called fratricide. Released DNA is taken up by competent cells and can serve as a source of new genetic material. The proteins involved in fratricide and fratricide immunity are highly conserved among pneumococci and other related strep species limiting the target population for lysis to members of the population that have failed to induce competence. The production of lytic pneumococcal bacteriocins (pneumocins) from the blp locus has the potential to expand the target range for DNA release. The blp locus is controlled by a parallel quorum sensing system to that required for competence induction. A number of genes in the blp locus have been shown to be upregulated during early competence induction and we have demonstrated that stimulation of competence induces transcription of the pneumocin genes in some isolates. Because the pneumocins and their immunity proteins encoded in the blp cluster are variable from strain to strain, they can promote lysis of a wide range of pneumococci and related streptococcal species independent of the competence state of the target. We hypothesize that coordinate expression of pneumocins with the competence state will increase the potential target organisms for DNA release and uptake. In Aim1 of the proposal we will investigate the mechanism of cross stimulation of pneumocin by competence induction. In Aim 2 we will determine the role of the regulatory proteins CiaRH and HtrA in controlling the cross talk between the blp and com systems. In Aim3, we will verify that coordinate blp/com regulation increases the target range for DNA release by demonstrating that pneumocin producing strains have an advantage over strains that rely solely on fratricide in the acquisition of foreign DNA. DNA exchange events will be studied in vitro under optimized conditions and in vivo, during mouse nasal colonization. The persistence of this pathogen despite ongoing attempts at clearance from both the host and the surrounding flora is a testament to the power of genomic diversity and adaptation. Understanding how the variably expressed pneumocins contribute to this diversity will allow us to better anticipate and perhaps block attempts at escape from control measures via genetic exchange.

描述（由申请人提供）：肺炎链球菌（肺炎球菌）是一种重要的人类病原体，是细菌性脑膜炎，肺炎和耳炎培养基的最常见原因。尽管它可能引起严重的疾病，但肺炎球菌是正常鼻咽菌群的一部分。它具有携带和掺入外源DNA的能力使肺炎球菌能够通过提供遗传适应的资源来抵抗清除尝试的尝试。基因组分析表明，该物种的特征是大量的遗传多样性主要来自其他链球菌的DNA。肺炎球菌中的能力状态受COM系统控制的法定感应系统的调节，该系统驱动了大量基因的产生，包括参与DNA摄取和重组的基因。有能力的肺炎球菌可以通过一种称为Fratricide的机制释放其DNA的人口中的非能力成员。释放的DNA被称职的细胞吸收，可以作为新遗传物质的来源。在肺炎球菌和其他相关的链球菌物种中，参与杂化和杂化剂免疫的蛋白质是高度保守的，这些链球菌限制了目标种群，以裂解降低未能诱导能力的人群的成员。 BLP基因座的裂解肺炎球菌（肺炎素）的产生有可能扩大DNA释放的靶范围。 BLP基因座由平行的群体传感系统控制到能力诱导所需的系统。 BLP基因座中的许多基因已显示在早期能力诱导期间被上调，我们证明了能力刺激在某些分离株中诱导肺炎素基因的转录。由于在BLP簇中编码的肺炎蛋白及其免疫蛋白从菌株到应变都是可变的，因此它们可以促进裂解广泛的肺炎球菌和相关的链球菌物种，而与靶标的能力无关。我们假设肺炎肺炎与能力状态的坐标表达将增加潜在的靶标生物以释放和摄取DNA。在该提案的AIM1中，我们将通过能力诱导研究肺炎的交叉刺激机制。在AIM 2中，我们将确定调节蛋白CIARH和HTRA在控制BLP和COM系统之间的交叉谈话中的作用。在AIM3中，我们将验证坐标BLP/COM调节通过证明肺炎毒素产生菌株比仅依赖于逆性外源DNA的菌株具有优势来增加DNA释放的目标范围。在优化的条件下和体内，在小鼠鼻腔定殖期间，将在体外研究DNA交换事件。尽管从宿主和周围的植物群进行了持续的清理尝试，但这种病原体的持续存在证明了基因组多样性和适应性的力量。了解可变表达的肺气素如何促进这种多样性，这将使我们能够更好地预期，也许可以通过遗传交换逃避控制措施的尝试。