Lipoprotein expresion and adaptation of B. burgdorferi

描述(申请人提供)：伯氏疏螺旋体导致哺乳动物持续感染，尽管对病原体产生了强烈的免疫反应。为了避免免疫清除，伯氏杆菌必须进化出免疫逃避策略。一种很有特色的策略是VISE抗原变异。他们假设了伯氏杆菌可能用来逃避免疫清除的另外两种机制：(1)下调暴露在表面的和抗体靶标的脂蛋白，以及(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。通过分析137个可能的脂蛋白基因在小鼠感染过程中的表达，他们确定了伯氏杆菌的一个两步分子适应过程。对于第一步，无论最初接种的伯氏杆菌表达137个脂蛋白基因中的全部还是不到40个，螺旋体都会在感染后10天内转录116个基因。在感染后17至30天的第二步中，免疫选择压力迫使伯氏杆菌下调大多数HAD基因，但表达116个基因中的33个。这一适应过程可能是伯氏杆菌进行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，他们将在B细胞缺陷小鼠和T细胞缺陷小鼠身上剖析这两种反应对伯氏杆菌适应的影响。为了充分探索这一假说，他们还将检查免疫选择压力对伯氏杆菌在TICK载体中适应的影响，以及针对单个脂蛋白的特异性抗体对小鼠宿主基因表达的影响。 尽管大多数伯氏杆菌脂蛋白基因表达下调，但所有已知的配体结合脂蛋白在慢性感染过程中持续表达，包括核心蛋白结合蛋白A和B、纤维连接蛋白结合蛋白和ERP蛋白。这是第二个假设的基础，即Bufgdorfer获得宿主成分并保护自己免受免疫清除。在这个项目中，他们还将使用核心蛋白缺乏的小鼠来检验这一假设。

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.