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

摘要 莱姆病的病例数是美国所有病媒传播疾病病例数的十倍， 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-疏螺旋体后 burgdorferi-患者经历轻微的流感样症状，可以继续变得更加严重。在后期阶段， 即使在抗生素治疗后，患者仍可能出现心脏、关节和神经系统问题。原因（S） 对持续性症状了解甚少，也是该领域争论最多的话题。这件事的首席调查员 提案发现，B. burgdorferi脱落约45%的肽聚糖（PG）-- 细菌细胞壁-从细胞内部进入其环境。B。在滑膜中可检测到伯氏PG 莱姆关节炎患者口服和/或静脉注射抗生素后数月的体液。当注射到小鼠体内时，B。 单独的burgdorferi PG能够引起关节炎。事实上，所有细菌都有PG，但事实证明，B。 burgdorferi PG在化学上是独特的，不同于任何先前研究的。实时PG跟踪实验 活体动物表明B的独特特征。Burgdorferi胞苷肽有助于半衰期和 离散组织定位。这些发现使我们假设脱落B。伯氏PG片段含有 持久性、莱姆病发病机制和关节炎所需的独特化学特征。这 一个建议将严格测试这些理论，并提供全面的理解1）如何和2）在哪里 PG能够持续存在; 3）什么样的分子特征有助于PG持续存在; 4） PG诱导的莱姆关节炎的基础;和5）在B的自然生命周期中，尿肽脱落的重要性。 burgdorferi。我们提出的研究挑战了传统思维，并可能导致我们如何改变我们的思维模式。 了解莱姆病的发病机制。他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.