The natural release of unusual peptidoglycan fragments drives persistent Lyme disease symptoms in susceptible hosts

异常肽聚糖片段的自然释放导致易感宿主持续出现莱姆病症状

• 批准号: 10736544
• 负责人: Brandon Lyon Jutras
• 金额: $ 56.19万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736544
• 关键词: Acute; Affect; Affective; Aftercare; American; Anatomy; Animal Experiments; Animals; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antigens; Arthritis; Automobile Driving; Bacteria; Biopolymers; Borrelia; Borrelia burgdorferi; Cardiac; Cell Wall; Cells; Chemicals; Chemistry; Chronic; Clinical; Comparative Study; Coupled; Data; Diagnosis; Disease; Environment; Etiology; Genetic; Growth; Health; Human; Impairment; Incidence; Infection; Inflammation; Integration Host Factors; Intravenous; Isotope Labeling; Knowledge; Label; Lead; Lyme Arthritis; Lyme Disease; Mammals; Methods; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mouse Strains; Mus; Nature; Oral; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Peptidoglycan; Phase; Planets; Play; Polymers; Predisposition; Reporting; Research Personnel; Role; Sampling; Severities; Symptoms; Synovial Fluid; System; Techniques; Therapeutic; Ticks; Time; Tissues; Toxin; Vector-transmitted infectious disease; Virulence Factors; experience; flu; genetic approach; human pathogen; immunoregulation; improved; in vivo; insight; lens; lyme pathogenesis; mouse genetics; mouse model; mutant; neuromusculoskeletal; nonhuman primate; pathogen; pathogenic bacteria; persistent symptom; response; reverse genetics

ABSTRACT Lyme disease is the most reported vector-borne disease in the Northern Hemisphere. Lyme disease is caused by the spirochetal bacterium¾Borrelia burgdorferi¾an unusual pathogen in that it is capable of causing severe disease, despite lacking any recognizable virulence factors. Prompt therapy is often affective, but many patients may still experience severe symptoms, chiefly Lyme arthritis. The reason(s) for persistent symptoms is poorly understood and the most debated topic in the field. The lead investigator of this proposal discovered that B. burgdorferi sheds ~45% of its peptidoglycan (PG)—the essential component of the bacterial cell-wall—from inside the cell, into its environment. B. burgdorferi PG can be detected in the synovial fluid of Lyme arthritis patients' months after oral and/or intravenous antibiotics. Experimental animal studies have shown that purified B. burgdorferi PG alone, is capable of causing arthritis. We have shown that the chemical constituents of B. burgdorferi PG are unlike any on the planet and real-time tracking studies indicate that these unique features are associated with extended dwell times in discrete organs. Taken together, we hypothesize that the natural release of unique B. burgdorferi PG fragments is responsible for driving Lyme arthritis, post-therapy, in susceptible mammals, but we can target lingering fragments for therapeutic purposes. This proposal will critically assess 1) what exactly is being released and what persists; 2) where and how the material persists; 3) the relationship between Borreliae PG chemistry and persistent disease; 4) host factors that may contribute to PG- induced arthritis; and 5) if targeted monoclonal antibody therapy is viable approach to treat patients suffering from Lyme arthritis. Our studies will fill critical knowledge gaps in what is driving patient symptomology after antibiotic therapy and may lead to new ways to treat patients when conventional options have failed.

抽象的 莱姆病是北半球报道最多的媒介传播疾病。 伯氏疏螺旋体 (Borrelia burgdorferi) 螺旋体细菌是一种不寻常的病原体，能够引起严重的 尽管缺乏任何公认的毒力因子，但对许多患者来说，及时治疗往往是有效的。 可能仍会出现严重症状，主要是莱姆关节炎。持续症状的原因尚不清楚。 该提案的首席研究员发现 B. 伯氏疏螺旋体从细菌中脱落约 45% 的肽聚糖 (PG)，这是细菌细胞壁的重要组成部分。 在莱姆关节炎的滑液中可以检测到细胞内的伯氏疏螺旋体 PG。 患者口服和/或静脉注射抗生素数月后的实验动物研究表明，纯化的抗生素。 伯氏疏螺旋体 PG 本身就能够引起关节炎。我们已经证明，伯氏疏螺旋体的化学成分。 burgdorferi PG 与地球上的任何一种都不同，实时跟踪研究表明这些独特的功能 与离散器官中的停留时间延长有关，我们追求的是自然的。 独特的伯氏疏螺旋体 PG 片段的释放是导致治疗后莱姆关节炎的原因 哺乳动物，但我们可以针对挥之不去的碎片进行治疗，这一提议将非常容易受到影响。 评估 1) 到底释放了什么以及持续存在什么；2) 材料在何处以及如何持续；3) 伯氏疏螺旋体 PG 化学与持续性疾病之间的关系；4) 可能导致 PG- 的宿主因素 5) 靶向单克隆抗体疗法是否是治疗患有此病的患者的可行方法 我们的研究将填补莱姆关节炎患者症状学的关键知识空白。 抗生素疗法可能会在传统选择失败时带来新的治疗方法。