A microbial antigen as a molecular trigger of Lyme borreliosis

描述（由申请人提供）：我们建议确定伯氏疏螺旋体表面暴露的蛋白质之一Lmp1是否以及如何作为诱导宿主炎症反应的分子触发器。关节炎是莱姆病最常见的临床并发症之一，是由细菌病原体伯氏疏螺旋体感染引起的。如果没有适当的治疗，大约60%的感染患者会表现为关节炎。炎症细胞（主要是中性粒细胞）的严重浸润是莱姆病的一个主要特征，它会导致感染关节的严重病理损伤。先前的研究表明，伯氏疏螺旋体具有强效的细胞因子刺激特性，螺旋体脂蛋白诱导促炎细胞因子的产生。我们最近对一个伯氏疏螺旋体基因产物的研究表明，抗原Lmp1，也被标记为表面定位的膜蛋白1，是莱姆病病原体的毒力决定因素。Lmp1的存在有助于螺旋体逃避宿主的适应性免疫反应。我们的初步数据表明，尽管lmp1缺陷的伯氏疏螺旋体在严重联合免疫缺陷（SCID）小鼠中持续存在，但与野生型螺旋体不同，这些等基因突变体不能诱导严重疾病。我们假设Lmp1可能有助于宿主炎症反应，从而导致莱姆病的并发症。本提案的目的是研究Lmp1作为宿主炎症反应的分子触发器的潜在作用。本研究将为莱姆病的发病机制提供新的认识，并有助于制定预防莱姆病关节炎的措施。

DESCRIPTION (provided by applicant): We propose to determine whether and how one of the Borrelia burgdorferi surface exposed proteins, Lmp1, functions as a molecular trigger for the induction of host inflammatory responses. Arthritis is one of the most frequent clinical complications of Lyme borreliosis, which results from the infection with the bacterial pathogen Borrelia burgdorferi. Without proper treatment, arthritis is manifested in approximately 60% of the infected patients. A severe infiltration of the inflammatory cells (mostly neutrophil) is a majr feature of Lyme arthritis that contributes to severe pathological damage in the infected joint. Previous studies have demonstrated that B. burgdorferi possesses potent cytokine-stimulating properties and that spirochete lipoproteins induce the production of pro-inflammatory cytokines. Our recent studies involving one of the B. burgdorferi gene products showed that the antigen Lmp1, also annotated as surface-located membrane protein 1, is a virulence determinant of the Lyme disease pathogen. The presence of Lmp1 assists the spirochete to evade host adaptive immune responses. Our preliminary data suggests that although Lmp1-deficient B. burgdorferi persists in severe combined immunodeficient (SCID) mice, unlike wild type spirochetes, these isogenic mutants are unable to induce severe disease. We hypothesize that Lmp1 could contribute to host inflammatory responses subsequently leading to the complications of Lyme borreliosis. The goal of this proposal is to study the potential role of Lmp1 as a molecular trigge of host inflammatory responses. This study will provide new insights into the pathogenesis of Lyme borreliosis and help developing preventive measures against Lyme arthritis. PUBLIC HEALTH RELEVANCE: Lyme borreliosis is an inflammatory disorder caused by the pathogen Borrelia burgdorferi during infection susceptible mammalian hosts, including humans. We propose to characterize the function of a surface-exposed virulence determinant of B. burgdorferi, which is critical for pathogen persistence and the genesis of diseases. This information will contribute to our understanding of molecular adaptation of pathogen in the host and the development of preventive measures against Lyme borreliosis.