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: 10001426
• 负责人: ANDREW T ULIJASZ
• 金额: $ 47.69万
• 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/10001426
• 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; Pneumonia; 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; crystallinity; design; human disease; human pathogen; inhibitor/antagonist; insight; mortality; mutant; negative affect; novel; novel therapeutics; particle; pathogen; prevent; preventable death; promoter; response; small molecule; structural biology; structured data; success; sugar; transcription factor; 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令人衰弱的人类病原体之一，在美国是最大的 尽管有可用的疫苗，但社区的常见原因还是获得了细菌性肺炎。作为 疫苗只能包含免疫力所需的一些菌株，我们必须找到其他治疗方法 靶向这种致命病原体的所有93多种不同版本（或血清型）。最大的问题之一 肺炎球菌研究正在理解这种病原体如何从无害的鼻腔中快速转化 与侵入性病原体的共生。理解这种关键过渡的关键是对S的调节。 肺炎最重要的毒力因素，它用于的保护性多糖（基于糖的）胶囊 避免我们的免疫系统。 我们的实验室现在已经确定了一组至关重要的蛋白质，它们在肺炎链球菌中一起起作用，并基于它们 高保护可能会导致侵入性和疾病。我们命名了 集体蛋白和小分子调节该过程的胶囊调节级联反应或CRC。在 这项工作我们将阐明CRC如何使S. Pneumonaie通过了解 该信号网络的分子和细胞相互作用。我们实现此目标的方法将包括 通过可视化其在整个活体动物中的作用，在最小的层（原子）中查看CRC 即时的。我们的研究结果将为这种病原体如何使用CRC提供前所未有的见解 引起疾病，为针对所有血清型的新型治疗策略铺平了道路，而不仅仅是 当前疫苗中包含的子集。最后，CRC与人类中的蛋白质分享 人类疾病的关键调节剂，例如癌症，心肌病和癫痫。因此，我们预测我们的 数据将对这些和其他人类疾病所表现出的机制有价值的见解。