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（Lyme 疾病是一个升级和普遍的问题。感染莱姆病剂 - 波罗利亚 Burgdorferi - 患者会经历温和的流感样符号，可能会变得更加严重。在以后的阶段， 即使经过抗生素治疗，患者也会遇到心脏，关节和神经系统问题。原因 持续的症状知之甚少，是该领域最有争议的话题。首席调查员 提案发现，B。burgdorferi掉了约45％的辣椒糖（PG） - 细菌细胞壁 - 从细胞内到其环境。 B.可以在滑膜上检测到Burgdorferi PG 口服和/或静脉注射抗生素几个月后，莱姆关节炎患者的液体。注入鼠标时，B。 仅Burgdorferi PG，能够引起关节炎。实际上，所有广播都有PG，但事实证明，B。 Burgdorferi PG在化学上是独一无二的，与任何先前研究的不同。实时的PG跟踪实验 活体动物表明，B。burgdorferi mulopepides的独特特征既有助于半衰期，又有助于 离散组织定位。这些发现导致我们假设棚屋B. burgdorferi pg碎片包含 持久性，莱姆病发病机理和关节炎所需的独特化学特征。这 提案将对这些理论进行批判性检验，并提供对1）如何和2）的全面理解 PG能够坚持下去； 3）哪些分子特征有助于PG持久性； 4）机械细节 PG诱导的莱姆关节炎基础； 5）在B. 伯格多尔里。我们拟议的研究挑战传统思维，并可能导致我们的方式改变 了解莱姆病发病机理。他们还可能导致新的治疗患者患者的新方法 疾病和治疗后莱姆病综合征，即使在常规疗法失败之后。