Virulence Determinants of the Lyme Disease Spirochete

描述（由申请人提供）：莱姆病是一种多系统、多阶段的炎症性疾病，由蜱传螺旋体伯氏疏螺旋体引起。在北美，莱姆关节炎是该病的主要表现。虽然炎症直接导致B的持续存在。尽管伯氏疏螺旋体抗原在持续性关节炎中起重要作用，但对参与感染和发病机制的疏螺旋体蛋白知之甚少。我们的长期目标是阐明毒力决定因素和毒力机制，作为制定治疗方案的先决条件，用于治疗莱姆关节炎和预防疾病。本申请的目的是鉴定对莱姆病重要的新的疏螺旋体毒力因子和免疫原。本研究基于我们最近的发现，即Hk 2-Rrp 2双组分信号通路，这是哺乳动物宿主中疏螺旋体毒力所必需的，控制一组与B的肠道感染相关的免疫原的表达。burgdorferi。我们推测这些免疫原在疏螺旋体感染和发病机制中起重要作用。为了验证这一假设，我们提出：1）鉴定由Hk 2-Rrp 2双组分信号通路控制的哺乳动物感染相关免疫原; 2）在B强毒株中构建产生这些免疫原的缺陷的同基因突变体。burgdorferi，以及3）检查突变体感染小鼠并在小鼠莱姆关节炎模型中引起疾病的能力。 相关性：实现本提案中概述的具体目标将可能导致发现在哺乳动物宿主中对疏螺旋体感染和发病机理至关重要的新毒力因子，这不仅将促进我们对莱姆病发病机理的分子机制的理解，而且将鉴定用于预防和治疗莱姆病关节炎的新的潜在疫苗靶点，和/或用于莱姆病的血清学测试的试剂。

DESCRIPTION (provided by applicant): Lyme disease is a multisystem, multistage, inflammatory illness caused by the tick-borne spirochete, Borrelia burgdorferi. In North America, Lyme arthritis is the major manifestation of the disease. Although inflammation directed at persistence of B. burgdorferi antigens plays an important role in persistent arthritis, little is known about the Borrelia proteins involved in infection and pathogenesis. Our long-term goal is to elucidate virulence determinants and mechanisms of virulence as a prerequisite to developing therapeutic protocols for treatment of Lyme arthritis and prevention of the disease. The objective of this application is to identify new Borrelia virulence factors and immunogens that are important for Lyme borreliosis. The proposed research is based on our recent finding that the Hk2-Rrp2 two-component signaling pathway, which is essential for Borrelia virulence in the mammalian host, governs expression of a group of mammalianinfection associated immunogens of B. burgdorferi. We hypothesize that these immunogens play important roles in Borrelia infection and pathogenesis. To test this hypothesis, we propose 1), to identify the mammalian infection-associated immunogens controlled by the Hk2-Rrp2 two-component signaling pathway; 2), to construct isogenic mutants defective in producing these immunogens in a virulent strain of B. burgdorferi, and 3) to examine the mutants' ability to infect mice and cause disease in the murine Lyme arthritis model. RELEVANCE: Accomplishing the specific aims outlined in this proposal will likely yield the discovery of new virulence factors that are essential for Borrelia infection and pathogenesis in mammalian hosts, which will not only advance our understanding the molecular mechanism of the pathogenesis of Lyme disease, but also will identify new potential vaccine target(s) for prevention and treatment of Lyme arthritis, and/or an agents of serological tests for Lyme disease.