Lipoprotein expresion and adaptation of B. burgdorferi

描述（由申请人提供）：伯氏疏螺旋体引起持续的哺乳动物感染，尽管对病原体产生了强烈的免疫反应。为了避免免疫清除，伯氏疏螺旋体必须进化出免疫逃避策略。一种很好表征的策略是VIsE抗原变异。他们假设伯氏疏螺旋体可能利用两种额外的机制逃避免疫清除：(1)下调表面暴露和抗体靶向脂蛋白，(2)获得宿主成分并保护自己。他们在解决第一个假设方面取得了进展。通过对小鼠感染过程中137个假定的脂蛋白基因的表达分析，他们确定了伯氏疏螺旋体的两步分子适应过程。在第一步中，无论最初接种的伯氏疏螺旋体是否表达了137个脂蛋白基因中的全部或少于40个，在感染后10天内调节螺旋体转录116个基因。在感染后17至30天的第二阶段，免疫选择压力迫使伯氏疏螺旋体下调大部分基因，但表达116个基因中的33个。这一适应过程可能是伯氏疏螺旋体进入慢性感染的关键步骤，因为如果螺旋体未能经历这一过程，病原体将在感染的早期阶段被清除。免疫选择压力包括体液免疫反应和细胞免疫反应。在这个项目中，他们将使用b细胞缺陷小鼠和t细胞缺陷小鼠解剖这两种反应对伯氏疏螺旋体适应的影响。为了充分探索这一假设，他们还将研究免疫选择压力对蜱媒介中伯氏疏螺旋体适应的影响，以及针对个体脂蛋白的特异性抗体对小鼠宿主基因表达的影响。

DESCRIPTION (provided by applicant): Borrelia burgdorferi causes persistent mammalian infection despite the development of strong immune responses to the pathogen. To avoid immune clearance, B. burgdorferi must evolve immune evasion strategies. One well-characterized strategy is VIsE antigenic variation. They have hypothesized two additional mechanisms that B. burgdorferi potentially uses to escape immune clearance: (1) to down regulate surface-exposed and antibody-targeted lipoproteins, and (2) to gain host components and protect itself. They have made progress toward addressing the first hypothesis. Through an analysis of expression of 137 putative lipoprotein genes on the course of murine infection, they have identified a two-step molecular adaptation process by B. burgdorferi. For the first step, regardless whether the initial inocula of B. burgdorferi express either all of or less than 40 of the 137 lipoprotein genes, the spirochetes are modulated to transcribe 116 of the genes within 10 days post-infection. During the second step, which occurs between 17 and 30 days post-infection, immune selection pressure forces B. burgdorferi to down-regulate most have, but expresses 33 of the 116 genes. This adaptation process could be a critical step for B. burgdorferi to proceed to chronic infection since the pathogen would be cleared at the early stage of infection if the spirochete failed to undergo the process. Immune selection pressure consists of humoral and cellular immune responses. In this project, they will dissect the influence of both responses on B. burgdorferi adaptation using B-cell-deficient mice and T-cell-deficient mice. To fully explore the hypothesis, they will also examine the influence of immune selection pressure on B. burgdorferi adaptation in the tick vector, and the influence of specific antibodies to individual lipoproteins on gene expression in the murine host. Although most of B. burgdorferi lipoprotein genes are down regulated, all known ligand-binding lipoproteins are persistently expressed during chronic infection, including decorin-binding proteins A and B, fibronectin-binding protein, and Erp proteins. This is the basis for the second hypothesis that B. bufgdorfer gains host components and protects itself from immune clearance. In this project, they will also examine this hypothesis using decorin-deficient mice.