Lipoprotein expresion and adaptation of B. burgdorferi

伯氏疏螺旋体的脂蛋白表达和适应

• 批准号: 7104373
• 负责人: FANG-TING LIANG
• 金额: $ 12.16万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104373
• 关键词: Borrelia; Lyme disease; SCID mouse; SDS polyacrylamide gel electrophoresis; Spirochaetales; antigen antibody reaction; bacteria infection mechanism; bacterial proteins; cellular immunity; decorin; disease vectors; environmental adaptation; enzyme linked immunosorbent assay; gene expression; host organism interaction; humoral immunity; laboratory mouse; membrane proteins; microarray technology; molecular cloning; polymerase chain reaction; protein binding; protein deficiency; surface antigens; ticks

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.

描述（由申请人提供）：尽管伯氏疏螺旋体对病原体产生了强烈的免疫反应，但仍会导致哺乳动物持续感染。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。一种充分表征的策略是 VIsE 抗原变异。他们假设伯氏疏螺旋体可能利用两种额外机制来逃避免疫清除：（1）下调表面暴露和抗体靶向的脂蛋白，以及（2）获得宿主成分并保护自身。他们在解决第一个假设方面取得了进展。通过分析 137 个假定的脂蛋白基因在小鼠感染过程中的表达，他们确定了伯氏疏螺旋体的两步分子适应过程。第一步，无论伯氏疏螺旋体的初始接种物表达 137 个脂蛋白基因中的全部还是少于 40 个，螺旋体都会在感染后 10 天内被调节转录 116 个基因。第二步发生在感染后 17 至 30 天之间，免疫选择压力迫使伯氏疏螺旋体下调 116 个基因中的大多数基因，但表达其中的 33 个。这种适应过程可能是伯氏疏螺旋体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，病原体将在感染早期被清除。免疫选择压力由体液免疫反应和细胞免疫反应组成。在这个项目中，他们将使用 B 细胞缺陷小鼠和 T 细胞缺陷小鼠来剖析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载体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鼠宿主基因表达的影响。 尽管大多数伯氏疏螺旋体脂蛋白基因下调，但所有已知的配体结合脂蛋白在慢性感染期间持续表达，包括核心蛋白聚糖结合蛋白A和B、纤连蛋白结合蛋白和Erp蛋白。这是第二个假设的基础，即 B. bufgdorfer 获得宿主成分并保护自身免受免疫清除。在这个项目中，他们还将使用核心蛋白聚糖缺陷小鼠来检验这一假设。