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

摘要 莱姆的病例比美国所有媒介传播疾病的总和多十倍 疾病是一个不断升级和普遍存在的问题。感染莱姆病病原体-疏螺旋体 Burgdorferi-患者出现轻微的流感样症状，可能会变得更严重。在后来的阶段， 即使在抗生素治疗之后，患者也会遇到心脏、关节和神经问题。原因(S) 人们对持续性症状知之甚少，也是该领域争论最多的话题。这件事的首席调查者 一项研究发现，伯氏杆菌分泌约45%的肽聚糖(PG)--伯氏杆菌的基本成分 细菌细胞壁--从细胞内进入细胞环境。滑膜中可检出伯氏杆菌Pg 莱姆关节炎患者口服和/或静脉注射抗生素后几个月的体液。当注射到小鼠体内时，B。 光是伯氏杆菌PG就能引起关节炎。几乎所有的细菌都有PG，但事实证明，B。 Burgdorferi PG在化学上是独一无二的，不同于以往任何研究。的实时PG跟踪实验 活体动物表明，伯氏杆菌多肽的独特特性有助于半衰期和半衰期 离散组织定位。这些发现使我们推测，伯氏杆菌PG片段中含有 独特的化学特征(S)，是持久力、莱姆病发病机制和关节炎所必需的。这 建议书将批判性地检验这些理论，并提供对1)如何以及2)在哪里的全面理解 PG的持久性；3)PG持久性的分子特征；4)PG持久性的机制细节 在PG诱导的莱姆关节炎的基础上；5)鼠多肽脱落在B。 勃格多费里。我们提议的研究挑战传统思维，并可能导致我们如何 了解莱姆病的发病机制。它们还可能导致治疗莱姆病患者的新方法 疾病和治疗后莱姆病综合征，即使在常规治疗失败后。

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.