Characterizing the Function of the Periplasmic Protease Tsp in Chlamydial Secondary Differentiation

周质蛋白酶 Tsp 在衣原体二次分化中的功能特征

• 批准号: 10666924
• 负责人: Derek James Fisher
• 金额: $ 24.06万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666924
• 关键词: Adult; Asthma; Bacteria; Biochemical; Biology; Blindness; C-terminal processing peptidase; CRISPR interference; Cell Wall; Cell division; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chronic; Data; Dependence; Developed Countries; Developing Countries; Development; Disease; Elements; Ensure; Enzymes; Escherichia coli; Genes; Genetic; Genetic Techniques; Genetic Transcription; Genome; Goals; Gram-Negative Bacteria; Growth; Growth and Development function; Healthcare Systems; Heart Diseases; Homeostasis; Human; In Vitro; Incidence; Infertility; Link; Lipids; Lipoproteins; Membrane; Metabolic; Modification; Morbidity - disease rate; Morphology; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pelvic Inflammatory Disease; Penicillin-Binding Proteins; Peptide Hydrolases; Peptidoglycan; Periplasmic Proteins; Phase; Pneumonia; Process; Proteins; Proteomics; Reiter Disease; Relaxation; Reporting; Respiratory Tract Infections; Role; Sexually Transmitted Diseases; Stress; Symptoms; System; Therapeutic; Therapeutic Agents; Time; Trachoma; Work; antimicrobial; candidate validation; crosslink; design; human pathogen; in vivo; infection burden; knock-down; normal microbiota; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; periplasm; prevent; protein degradation; stem; therapeutic target; tool; tubal infertility

Project Summary: Characterizing the Function of the Periplasmic Protease Tsp in Chlamydial Secondary Differentiation Chlamydia is an obligate intracellular bacterial pathogen that causes a range of serious diseases in humans. In developed countries, Chlamydia trachomatis is the primary cause of bacterial sexually transmitted infections (STI). Indeed, recent reports from the Centers for Disease Control highlight the increasing incidence of STIs, with chlamydia infections consistently outpacing all other types. In developing countries, C. trachomatis is not only a significant cause of STI, but it is also responsible for the primary cause of infectious preventable blindness, trachoma. The major concern of chlamydial infections is that they are often asymptomatic and undiagnosed, which can lead to chronic sequelae. These include pelvic inflammatory disease, tubal factor infertility, and reactive arthritis for C. trachomatis. Consequently, chlamydial diseases remain a significant burden on health care systems around the world. In adapting to obligate intracellular growth, Chlamydia has significantly reduced its genome size and eliminated genes from various pathways as it relies on the host cell for its metabolic needs. This pathogen has also adapted to alternate between different functional and morphological forms during its normal growth, also referred to as its developmental cycle. These observations, combined with its obligate intracellular dependence, makes Chlamydia a difficult organism with which to work. However, recent development of genetic tools to study chlamydiae mechanistically have significantly enhanced our understanding of this pathogen. This proposal applies a combination of these new genetic techniques and classical biochemical studies to evaluate the role of a conserved periplasmic protease system in chlamydial growth and pathogenesis. The hypothesis of the proposed work is that Chlamydia uses this periplasmic protease to effect secondary differentiation from the replicative to the infectious form of the organism by degrading cell division- related proteins. This prevents further division of the replicative form as the bacteria differentiate. Major goals of this proposal are (i) to characterize the function of the periplasmic protease Tsp both in vitro and in vivo and (ii) to identify and validate substrates of Tsp. Results will advance our understanding of this important pathogen and lead to the design of novel therapeutic agents that are specific for Chlamydia. This in turn will allow for minimal effects on normal flora for patients receiving treatment for this highly prevalent disease.

项目摘要：表征神经蛋白酶TSP在衣原体中的功能 次要分化 衣原体是一种义务的细胞内细菌病原体，会导致一系列严重疾病 人类。在发达国家，沙眼衣原体是细菌性传播的主要原因 感染（STI）。确实，疾病控制中心的最新报告突出了发病率的增加 STI，衣原体感染始终超过所有其他类型。在发展中国家，C。 气管瘤不仅是STI的重要原因，而且还导致了传染性的主要原因 可预防的失明，沙眼。衣原体感染的主要关注点是它们经常是 无症状和未诊断，可能导致慢性后遗症。这些包括骨盆炎症 疾病，输卵管因子不育症和气管梭菌的反应性关节炎。因此，衣原体疾病 在世界各地的医疗保健系统上仍然承担重大负担。 为了适应义务细胞内生长，衣原体大大降低了其基因组大小和 从各种途径中消除了基因，因为它依靠宿主细胞来代谢需求。这种病原体 还适用于在正常生长期间不同功能和形态学形式之间的替代品， 也称为其发展周期。这些观察结果，结合了其专有的细胞内 依赖性使衣原体成为一个困难的有机体。但是，最近的发展 从机理上研究衣原体的遗传工具显着增强了我们对此的理解 病原。该提案采用了这些新遗传技术和经典生化的结合 评估保守的周质蛋白酶在衣原体生长和 发病。拟议工作的假设是衣原体使用这种周质蛋白酶作用 通过降解细胞分裂 - 相关蛋白质。这可以防止复制形式的进一步分裂，因为细菌分化。主要目标 该建议的（i）是表征周围蛋白酶TSP的功能，并在体外表征 （ii）识别和验证TSP的底物。结果将促进我们对这一重要的理解 病原体并导致针对衣原体特有的新型治疗剂的设计。反过来将 对于接受这种高度普遍疾病的治疗的患者，对正常菌群的影响最小。