Virulence Determinants of the Lyme Disease Spirochete

描述(申请人提供)：莱姆病是由壁虱传播的伯氏疏螺旋体引起的一种多系统、多阶段的炎症性疾病。在北美，莱姆关节炎是该病的主要表现。虽然针对伯氏杆菌抗原持久性的炎症在持续性关节炎中起着重要作用，但对涉及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，作为开发治疗莱姆关节炎和预防该病的治疗方案的先决条件。这项应用的目的是确定新的疏螺旋体毒力因子和免疫原，这些因素和免疫原对莱姆疏螺旋体病很重要。这项研究是基于我们最近的研究发现，在哺乳动物宿主中对疏螺旋体毒力至关重要的Hk2-RRP2双组分信号通路控制着一组与哺乳动物感染相关的伯氏疏螺旋体免疫原的表达。我们推测这些免疫原在疏螺旋体感染和致病过程中起重要作用。为了验证这一假设，我们建议1)鉴定由Hk2-RRP2双组分信号通路控制的哺乳动物感染相关免疫原；2)构建在伯氏杆菌强毒株中产生这些免疫原缺陷的等基因突变体；3)在小鼠莱姆关节炎模型中检测这些突变体感染小鼠并导致疾病的能力。 相关性：完成本提案中概述的特定目标可能会发现对哺乳动物宿主中的疏螺旋体感染和致病至关重要的新的毒力因子，这不仅将促进我们对莱姆病发病机制的分子机制的理解，还将发现用于预防和治疗莱姆病的新的潜在疫苗靶点(S)，和/或莱姆病的血清学测试试剂。

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.