Lyme arthritis virulence of Borrelia burgdorferi

描述(申请人提供)：莱姆病是一种复杂的多系统疾病，由伯氏疏螺旋体引起，是北美最常见的媒介传播疾病。莱姆关节炎是其主要表现之一。在小鼠模型中，包括关节炎在内的几个与人类莱姆病相似的特征一直被诱导出来。在严重联合免疫缺陷(SCID)小鼠模型中，伯氏杆菌感染会导致破坏性关节炎。伯氏杆菌基因组由一条染色体和多达21个线形和环状的质粒组成。伯氏杆菌的体外繁殖与质粒的丢失有关，而质粒的丢失与感染性和致病性的降低有关。我们已经产生了一种螺旋体变体，它在SCID小鼠中完全具有感染性，但在这个模型中无法诱导关节炎。质粒含量分析显示，在非致病变异体中，存在于关节炎毒力株中的四个质粒缺失，这表明这些质粒可能携带关节炎毒力基因。我们将首先确定哪种质粒对于关节炎的诱导是必不可少的。为了实现这一目标，将产生具有不同质粒含量的变异体，并检测其传染性和关节炎毒力。一旦确定了与关节炎相关的质粒，我们将能够专注于关节炎致病基因。在致炎质粒上编码的独特基因将被选择性地灭活，然后进行补充，以检测这些基因对关节炎诱导的影响。

DESCRIPTION (provided by applicant): Lyme disease is a complex multisystem disorder caused by the spirochete Borrelia burgdorferi and the most common vector-borne illness in North America. Lyme arthritis is one of the major manifestations. Several features that parallel human Lyme disease are consistently induced in the murine model, including arthritis. In the model of severe combined immunodeficiency (SCID) mice, B. burgdorferi infection causes destructive arthritis. The genome of B. burgdorferi consists of a chromosome and up to 21 linear and circular plasmids. In vitro propagation of B. burgdorferi is associated with plasmid loss and loss of plasmids is coupled with decreased infectivity and pathogenicity. We have generated a spirochete variant that is fully infectious in SCID mice but unable to induce arthritis in this model. Plasmid content analysis revealed that four plasmids that were present in arthritis-virulent strains had been missing from the nonpathogenic variant, suggesting that these plasmids may carry arthritis-virulent genes. We will first determine which of the plasmids are essential for the induction of arthritis. To achieve this goal, variants with different plasmid contents will be generated and examined for infectivity and arthritis virulence. Once arthritis-related plasmids are identified, we will be able to focus on arthritis-virulent genes. Unique genes encoded on the arthritis-virulent plasmids will be selectively inactivated and then complemented to examine the influence of these genes on the induction of arthritis.