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OspC regulation and pathogenic strategy of Borrelia burgdorferi

伯氏疏螺旋体OspC调控及致病策略

基本信息

批准号：
8511545
负责人：
FANG-TING LIANG
金额：
$ 34.09万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-20 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511545
关键词：
Acrodermatitis Address Animal Model Antibodies Antigens Arthritis Bacteria Borrelia Borrelia burgdorferi Carditis Complement Contracts Cutaneous DNA Binding DNA-Binding Proteins Deer Tick Disease Down-Regulation Electrophoretic Mobility Shift Assay Europe Expression Library Gene Expression Gene Expression Regulation Genes Goals Green Fluorescent Proteins Health Humoral Immunities Immune Immune system Immunity Immunocompetent In Vitro Infection Left Lesion Lipoproteins Lyme Disease Modeling Molecular Mus Nature Neurologic North America Order Spirochaetales OspA protein OspC protein Patients Phenotype Process Proteins Regulation Role SCID Mice Signal Transduction Surface Syndrome System Ticks United States base computer program erythema migrans genetic regulatory protein killings meetings mutant pathogen pressure promoter protein expression red fluorescent protein research study response screening vector

项目摘要

DESCRIPTION (provided by applicant): Lyme disease caused by the spirochete Borrelia burgdorferi is the most common vector-borne illness in North America. Coordinated expression of its surface lipoprotein antigens is crucial for its pathogenic strategy. B. burgdorferi abundantly produces outer surface protein A (OspA) in engorged and flat ticks but downregulates OspA and upregulates OspC in response to a bloodmeal. OspC expression ultimately elicits a robust humoral response that poses tremendous pressure on the pathogen. To evade the protective immunity, B. burgdorferi down-regulates ospC. We showed that the downregulation of OspA and OspC in the murine host is achieved via the involvement of newly identified ospC and ospA operators and hypothesize that B. burgdorferi down-regulates ospC and ospA via the interaction of the operators with as-yet unidentified regulatory proteins. This project will first focus on these regulators. In vitro systems will be used to identify these regulators in Aim 1; their essential roles attributed to the ability of B. burgdorferi to evade the immune system and cause persistent infection will be investigated in animal models in Aim 2. The project will be further expanded to explore mechanisms governing the downregulation of OspC. To achieve this goal we have outlined two hypotheses: selection vs. signaling. The molecular basis for the selection hypothesis is that B. burgdorferi generates multiple phenotypes during murine infection, such as spirochetes that abundantly express ospC and others that do not. OspC antibody selectively eliminates phenotypes that express ospC but allows others that do not express ospC to expand. For the signaling hypothesis, B. burgdorferi can sense specific antibody and selectively down-regulate ospC via the induction of the repressor. Aim 3 is proposed to either seek the molecular basis for the selection hypothesis, or to rule out the involvement of a killing process in the antibody-induced ospC down-regulation in the murine model. PUBLIC HEALTH RELEVANCE: Lyme disease caused by the spirochetal bacterium Borrelia burgdorferi, which is transmitted by deer ticks, is the most common vector-borne illness in North America and Europe. Over 20,000 people contract the disease annually in the United States alone. Lyme disease is a multi-system disorder that can result in arthritis, neurological abnormalities, carditis, and cutaneous lesions such as erythema migrans and acrodermatitis chronica atrophicans. If left untreated, the infection and disease may last years. Even worse, up to 10% of Lyme disease patients may develop post-Lyme syndrome, a mysterious illness that can not be cured. Tight regulation of gene expression is crucial for the pathogenic strategy of B. burgdorferi. The goal of the proposed study is to understand how B. burgdorferi regulates gene expression to meet its pathogenic strategy.

描述（由申请人提供）：由伯氏疏螺旋体引起的莱姆病是北美最常见的媒介传播疾病。其表面脂蛋白抗原的协调表达对其致病策略至关重要。伯氏疏螺旋体在充血和扁平蜱中大量产生外表面蛋白A (OspA)，但在血食反应中下调OspA和上调OspC。OspC的表达最终引起强烈的体液反应，对病原体造成巨大的压力。为了逃避保护性免疫，伯氏疏螺旋体下调ospC。我们发现OspA和OspC在小鼠宿主中的下调是通过新发现的OspC和OspA操作符的参与实现的，并假设伯氏疏螺旋体通过操作符与尚未确定的调节蛋白的相互作用来下调OspC和OspA。该项目将首先关注这些监管机构。体外系统将用于在Aim 1中识别这些调节剂；它们在伯氏疏螺旋体逃避免疫系统和引起持续感染的能力中所起的重要作用将在Aim 2的动物模型中进行研究。该项目将进一步扩大，以探索OspC下调的机制。为了实现这一目标，我们提出了两个假设：选择vs.信号传导。选择假说的分子基础是伯氏疏螺旋体在小鼠感染期间产生多种表型，如螺旋体大量表达ospC，而其他螺旋体则不表达ospC。OspC抗体选择性地消除表达OspC的表型，但允许其他不表达OspC的表型扩增。对于信号传导假说，伯氏疏螺旋体可以感知特异性抗体，并通过诱导抑制因子选择性下调ospC。目的3是寻求选择假说的分子基础，或者在小鼠模型中排除抗体诱导的ospC下调中涉及杀伤过程。公共卫生相关性：由鹿蜱传播的螺旋体细菌伯氏疏螺旋体引起的莱姆病是北美和欧洲最常见的媒介传播疾病。仅在美国，每年就有超过2万人感染这种疾病。莱姆病是一种多系统疾病，可导致关节炎、神经异常、心脏炎和皮肤病变，如移行性红斑和慢性萎缩性肢端皮炎。如果不及时治疗，感染和疾病可能持续数年。更糟糕的是，高达10%的莱姆病患者可能会患上莱姆病后综合症，这是一种无法治愈的神秘疾病。基因表达的严格调控对伯氏疏螺旋体的致病策略至关重要。本研究的目的是了解伯氏疏螺旋体如何调节基因表达以满足其致病策略。