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.

摘要 莱姆病是北方半球报告最多的病媒传播疾病。莱姆病是由 伯氏疏螺旋体（Borrelia burgdorferi）是一种不寻常的病原体，它能够引起严重的 疾病，尽管缺乏任何可识别的毒力因子。及时的治疗往往是有效的，但许多患者 可能仍然会出现严重的症状，主要是莱姆关节炎。持续症状的原因是不良的 这也是该领域最受关注和争议的话题。该提案的首席研究员发现，B。 伯氏菌的肽聚糖（PG）-细菌细胞壁的基本组成部分-从 进入细胞内部，进入环境。B。在莱姆关节炎的滑液中可检测到伯氏PG 患者口服和/或静脉注射抗生素后的月数。实验动物研究表明， B。单独的burgdorferi PG能够引起关节炎。我们已经证明了B的化学成分。 burgdorferi PG不同于地球上的任何一种，实时跟踪研究表明，这些独特的功能 与离散器官中延长的停留时间有关。综合起来，我们假设自然的 唯一B的释放。在治疗后，burgdorferi PG片段是导致莱姆关节炎的原因， 易感的哺乳动物，但我们可以针对挥之不去的片段进行治疗。该提案将批判性地 评估1）到底是什么被释放，什么持续存在; 2）在哪里和如何材料持续存在; 3） 疏螺旋体PG化学和持续性疾病之间的关系; 4）可能有助于PG- 诱导性关节炎;以及5）如果靶向单克隆抗体疗法是治疗患有 莱姆关节炎我们的研究将填补关键的知识空白，是什么驱动病人病理学后， 抗生素治疗，并可能在传统选择失败时找到治疗患者的新方法。