Virulence Determinants of the Lyme Disease Spirochete

描述（由申请人提供）：莱姆病是一种由蜱传螺旋体伯氏疏螺旋体引起的多系统、多阶段炎症性疾病。在北美，莱姆病是该病的主要表现。尽管针对伯氏疏螺旋体抗原持续性的炎症在持续性关节炎中起重要作用，但对伯氏疏螺旋体蛋白在感染和发病机制中的作用知之甚少。我们的长期目标是阐明毒力决定因素和毒力机制，作为制定治疗莱姆病和预防疾病的治疗方案的先决条件。本应用程序的目的是确定新的伯氏疏螺旋体毒力因子和免疫原是重要的莱姆病。该研究基于我们最近的发现，Hk2-Rrp2双组分信号通路控制伯氏疏螺旋体感染相关免疫原的表达，该信号通路对哺乳动物宿主的伯氏疏螺旋体毒力至关重要。我们推测这些免疫原在伯氏疏螺旋体感染和发病中起重要作用。为了验证这一假设，我们提出：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)构建在伯氏疏螺旋体毒力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突变体感染小鼠和致病的能力。

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.