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：表征衣原体周质蛋白酶 Tsp 的功能 二次分化 衣原体是一种专性细胞内细菌病原体，可引起一系列严重疾病 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（性传播感染）。事实上，疾病控制中心最近的报告强调了发病率的增加 性传播感染的发病率，其中衣原体感染率始终超过所有其他类型。在发展中国家，C. 沙眼衣原体不仅是性传播感染的重要原因，也是传染性疾病的主要原因 可预防的失明、沙眼。衣原体感染的主要问题是它们经常 无症状且未确诊，可能导致慢性后遗症。这些包括盆腔炎 沙眼衣原体疾病、输卵管因素不孕症和反应性关节炎。因此，衣原体疾病 仍然是世界各地医疗保健系统的重大负担。 为了适应专性细胞内生长，衣原体显着减小了其基因组大小并 从各种途径中消除基因，因为它依赖宿主细胞来满足其代谢需求。这种病原体 在正常生长过程中也适应了不同功能和形态形式的交替， 也称为其发育周期。这些观察结果，结合其专性细胞内 依赖性，使得衣原体成为一种难以处理的生物体。然而，最近的发展 从机制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。该提案结合了这些新的遗传技术和经典的生化技术 研究评估保守的周质蛋白酶系统在衣原体生长和 发病。这项工作的假设是衣原体利用这种周质蛋白酶来影响 通过降解细胞分裂，使生物体从复制形式二次分化为感染形式 相关蛋白质。这可以防止细菌分化时复制形式的进一步分裂。主要目标 该提案的目的是 (i) 表征周质蛋白酶 Tsp 的体外和体内功能 (ii) 识别和验证 Tsp 的底物。结果将加深我们对这一重要问题的理解 病原体并导致设计针对衣原体的新型治疗剂。这反过来又将 对于接受这种高度流行疾病治疗的患者来说，其对正常菌群的影响最小。