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（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，也是细菌性脑膜炎、肺炎和中耳炎的最常见原因。尽管肺炎球菌可引起严重疾病，但它是正常鼻咽菌群的一部分。肺炎球菌具有吸收和整合外源 DNA 的能力，能够为遗传适应提供资源，从而抵抗清除尝试。基因组分析表明，该物种的特点是具有大量的遗传多样性，主要来源于与其他链球菌 DNA 的重组。肺炎球菌的能力状态由 com 系统控制的群体感应系统调节，该系统驱动大量基因的产生，包括那些涉及 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自相残杀的机制来裂解群体中的无能力成员，释放其 DNA。释放的 DNA 被感受态细胞吸收，可以作为新遗传物质的来源。涉及自相残杀和自残免疫的蛋白质在肺炎球菌和其他相关链球菌物种中高度保守，将裂解的目标群体限制为未能诱导能力的群体成员。从 blp 基因座产生裂解性肺炎球菌细菌素（肺炎球菌素）有可能扩大 DNA 释放的目标范围。 blp 基因座由平行群体感应系统控制，以达到能力诱导所需的水平。 blp 基因座中的许多基因已显示在早期能力诱导过程中上调，并且我们已经证明，能力的刺激会诱导某些分离株中肺炎球菌素基因的转录。由于 blp 簇中编码的肺炎球菌素及其免疫蛋白因菌株而异，因此它们可以促进多种肺炎球菌和相关链球菌物种的裂解，而与目标的能力状态无关。我们假设肺炎球菌素的表达与能力状态的协调将增加 DNA 释放和摄取的潜在目标生物体。在该提案的目标 1 中，我们将研究通过能力诱导交叉刺激肺炎球菌素的机制。在目标 2 中，我们将确定调节蛋白 CiaRH 和 HtrA 在控制 blp 和 com 系统之间的串扰中的作用。在 Aim3 中，我们将验证协调 blp/com 调节增加了 DNA 释放的目标范围，方法是证明肺炎霉素生产菌株在获取外源 DNA 方面比仅依赖自相残杀的菌株具有优势。 DNA 交换事件将在优化条件下进行体外研究，并在小鼠鼻定植期间进行体内研究。尽管不断尝试从宿主和周围菌群中清除，但这种病原体的持续存在证明了基因组多样性和适应的力量。了解不同表达的肺炎球菌素如何促成这种多样性将使我们能够更好地预测并可能阻止通过基因交换逃避控制措施的尝试。