Defining the host and pathogen determinants of peptidoglycan induced pathophysiology in Lyme disease

定义莱姆病肽聚糖诱导的病理生理学的宿主和病原体决定因素

• 批准号: 10566961
• 负责人: Brandon Lyon Jutras
• 金额: $ 51.25万
• 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: 2023-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566961
• 关键词: Accounting; Acute; Adjuvant; Affect; Anabolism; Anatomy; Animals; Antibiotic Therapy; Antibiotics; Antigens; Arthritis; Automobile Driving; Bacteria; Biopolymers; Borrelia; Borrelia burgdorferi; Cardiac; Cell Wall; Cells; Chemicals; Chemistry; Chronic; Comparative Study; Complex; Cytotoxic T-Lymphocytes; Data; Disease; Environment; Epidemic; Functional disorder; Growth; Half-Life; Heart; Human; Immune response; Inbred Strains Mice; Incidence; Infection; Inflammation; Intravenous; Isotope Labeling; Joints; Label; Lead; Life Cycle Stages; Lyme Arthritis; Lyme Disease; Mediating; Molecular; Mus; Neurologic; Oral; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Peptidoglycan; Phase; Play; Post Treatment Lyme Disease Syndrome; Research Personnel; Resolution; Role; Severities; Specificity; Symptoms; Synovial Fluid; System; TLR2 gene; Techniques; Testing; Thinking; Ticks; Tissues; Toxin; United States; Vector-transmitted infectious disease; conventional therapy; experience; experimental study; flu; human pathogen; immune activation; immunoregulation; in vivo; innovation; insight; lens; lyme pathogenesis; mouse model; mutant; neuromusculoskeletal; novel; pathogen; pathogenic bacteria; persistent symptom; theories; virtual

ABSTRACT Accounting for ten times more cases than all of vector-borne diseases combined in the United States, Lyme disease is an escalating and pervasive problem. Upon infection with the Lyme disease agent—Borrelia burgdorferi— patients experience mild, flu-like symptoms that can go on to become more severe. In later stages, even after antibiotic therapy, patients can experience heart, joint, and neurological problems. 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. When injected into a mouse, B. burgdorferi PG alone, is capable of causing arthritis. Virtually all bacteria have PG but, as it turns out, B. burgdorferi PG is chemically unique and unlike any previously studied. Real-timing PG tracking experiments in live animals suggest that the unique features of B. burgdorferi muropeptides contributes to both half-life and discrete tissue localization. These findings led us to hypothesize that shed B. burgdorferi PG fragments contain unique chemical signature(s) that are required for persistence, Lyme disease pathogenesis, and arthritis. This proposal will critically test these theories and provide a comprehensive understanding of 1) how and 2) where PG is able to persist; 3) what molecular features contribute to PG persistence; 4) the mechanistic details that underlie PG-induced Lyme arthritis; and 5) the importance of muropeptide shedding in the natural life cycle of B. burgdorferi. Our proposed studies challenge conventional thinking and may lead to a paradigm shift in how we understand Lyme disease pathogenesis. They may also lead to novel ways to treat patients suffering with Lyme disease and post-treatment Lyme disease syndrome, even after conventional therapies have failed.

抽象的 莱姆病的病例数是美国所有媒介传播疾病病例总数的十倍 莱姆病病原体——伯氏疏螺旋体感染后，该病会不断升级且普遍存在。 伯氏疏螺旋体——患者会出现轻微的流感样症状，但在后期可能会变得更加严重。 即使经过抗生素治疗，患者仍可能出现心脏、关节和神经系统问题。 持续性症状尚不清楚，也是该领域争论最多的话题。 提案发现，伯氏疏螺旋体会释放出约 45% 的肽聚糖 (PG)，而肽聚糖是细菌的重要组成部分。 细菌细胞壁——从细胞内部进入其环境，可以在滑液中检测到伯氏疏螺旋体 PG。 莱姆关节炎患者口服和/或静脉注射抗生素几个月后的液体注射到小鼠体内时，B. 伯氏疏螺旋体 PG 本身就能够引起关节炎，几乎所有细菌都含有 PG，但事实证明，伯氏疏螺旋体 (B. burgdorferi PG 具有独特的化学性质，与之前研究的任何实时 PG 跟踪实验不同。 活体动物表明，伯氏疏螺旋体胞肽的独特特征有助于延长半衰期和 这些发现使我们发现，伯氏疏螺旋体的 PG 片段含有离散的组织定位。 持续性、莱姆病发病机制和关节炎所需的独特化学特征。 提案将批判性地测试这些理论，并提供对 1) 如何以及 2) 在何处的全面理解 PG 能够持续存在；3）哪些分子特征有助于 PG 持续存在；4）机制细节； PG 诱导的莱姆关节炎的基础；5) 胞壁肽脱落在 B. 我们提出的研究挑战了传统思维，并可能导致我们的方式发生范式转变。 了解莱姆病的发病机制，它们还可能带来治疗莱姆病患者的新方法。 疾病和治疗后莱姆病综合症，即使在常规疗法失败后。