A Regulatory Cascade that Controls Pneumococcal Capsule Biosynthesis

控制肺炎球菌胶囊生物合成的级联监管

• 批准号: 10216972
• 负责人: ANDREW T ULIJASZ
• 金额: $ 47.81万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216972
• 关键词: Address; Adherence; Affect; Age; Anabolism; Animals; Architecture; Bacteria; Bacterial Pneumonia; Biochemical; Cancer Etiology; Cardiomyopathies; Cells; Cessation of life; Characteristics; Child; Communities; Complex; Cryoelectron Microscopy; DNA; Data; Disease; Elderly; Elements; Environmental Risk Factor; Enzymes; Epilepsy; Genetic study; Glucose; Goals; Gram-Positive Bacteria; Human; Immune system; Immunity; Infection; Invaded; Life; Ligands; Lung; Malignant Neoplasms; Medical; Methods; Microbial Biofilms; Modeling; Molecular; Molecular Structure; Morbidity - disease rate; Mutation; Names; Nose; Operon; Oxygen; Pathogenesis; Phagocytosis; Phenotype; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Population; Process; Production; Proteins; Purines; Regulation; Research; Resolution; Role; Serotyping; Set protein; Signal Pathway; Signal Transduction; Streptococcus pneumoniae; Stress; Structure; System; Therapeutic; Time; Tissues; United States; Vaccines; Virulence; Virulence Factors; Visualization; Work; alternative treatment; antimicrobial; atomic interactions; base; biological systems; capsule; community acquired pneumonia; crystallinity; design; human disease; human pathogen; inhibitor/antagonist; insight; mortality; mutant; negative affect; novel; novel therapeutic intervention; particle; pathogen; prevent; preventable death; promoter; response; small molecule; structural biology; success; sugar; transcription factor; vaccine access; virtual

Project Abstract Streptococcus pneumoniae is one of the world's most debilitating human pathogens, and in the US is the most common cause of community acquired bacterial pneumoniae, despite having an available vaccine. As the vaccine can only contain some of the strains needed for immunity, we must find alternative treatments that target all 93+ different versions (or serotypes) of this deadly pathogen. One of the largest problems in pneumococcal research is understanding how this pathogen can quickly convert from a harmless nasal commensal to invasive pathogen. Key to understanding this crucial transition is the regulation of one of S. pneumoniae's most important virulence factors, the protective polysaccharide (sugar-based) capsule it uses to avoid our immune system. Our lab has now identified a crucial set of proteins that work together in S. pneumoniae, and based on their high conservation likely many other pathogens, to enable invasiveness and disease. We have named the collective proteins and small molecules that regulate this process the Capsule Regulatory Cascade, or CRC. In this work we will elucidate how the CRC enables S. pneumonaie to invade the lung by understanding the molecular and cellular interactions of this signaling network. Our methods to achieve this goal will include looking at the CRC at the smallest level (atoms), through visualization of its action within whole live animals in real time. Results from our studies will give unprecedented insight as to how this pathogen uses the CRC to cause disease, paving the way for novel therapeutic strategies targeting all serotypes rather than just the subset contained in the current vaccines. Finally, the CRC shares homology with proteins in humans that are crucial regulators of human disease, such as cancer, cardiomyopathy and epilepsy. We thus predict that our data will lend valuable insight into the mechanism by which these and other human diseases manifest.

项目摘要 肺炎链球菌是世界上最使人衰弱的病原体之一，在美国是最严重的。 尽管有可用的疫苗，但社区获得性细菌性肺炎的常见原因。作为 疫苗只能含有免疫所需的部分菌株，我们必须找到替代疗法 针对这种致命病原体的所有 93 种以上不同版本（或血清型）。最大的问题之一 肺炎球菌研究正在了解这种病原体如何从无害的鼻腔快速转化 与入侵病原体共生。理解这一关键转变的关键是对 S. 肺炎链球菌最重要的毒力因子是其用于保护性多糖（糖基）胶囊 避免我们的免疫系统。 我们的实验室现已鉴定出一组在肺炎链球菌中协同作用的关键蛋白质，并基于它们的 高度保守可能导致许多其他病原体的入侵和疾病。我们已将其命名为 调节这一过程的蛋白质和小分子的集合体称为胶囊调节级联（Capsule Regulatory Cascade，CRC）。在 在这项工作中，我们将通过了解 CRC 如何使肺炎链球菌侵入肺部 该信号网络的分子和细胞相互作用。我们实现这一目标的方法包括 通过可视化其在整个活体动物中的作用，从最小的水平（原子）观察 CRC 即时的。我们的研究结果将提供前所未有的见解，让我们了解这种病原体如何利用 CRC 来 引起疾病，为针对所有血清型而不仅仅是针对特定血清型的新治疗策略铺平了道路 当前疫苗中包含的子集。最后，CRC 与人类蛋白质具有同源性， 癌症、心肌病和癫痫等人类疾病的重要调节因子。因此我们预测我们的 数据将为了解这些疾病和其他人类疾病的表现机制提供有价值的见解。