OspC regulation and pathogenic strategy of Borrelia burgdorferi

伯氏疏螺旋体OspC调控及致病策略

• 批准号: 8113905
• 负责人: FANG-TING LIANG
• 金额: $ 36.26万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113905
• 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; Screening procedure; 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; vector

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）：莱姆病由螺旋体伯氏疏螺旋体引起，是北美最常见的病媒传播疾病。其表面脂蛋白抗原的协调表达是其致病策略的关键。B。在饱食和扁平蜱中，伯氏螺旋体大量产生外表面蛋白A（OspA），但响应于血粉下调OspA并上调OspC。OspC表达最终激发了对病原体造成巨大压力的强大体液应答。为了逃避保护性免疫，B。burgdorferi下调ospC。我们发现，在鼠宿主中OspA和OspC的下调是通过新鉴定的ospC和ospA操纵子的参与实现的，并假设B. burgdorferi通过操纵子与尚未鉴定的调节蛋白的相互作用下调ospC和ospA。本项目将首先关注这些监管机构。体外系统将用于鉴定目标1中的这些调节剂;它们的基本作用归因于B的能力。目的2中将在动物模型中研究伯氏螺旋体逃避免疫系统并引起持续感染的能力。该项目将进一步扩展，以探索OspC下调的机制。为了实现这一目标，我们概述了两个假设：选择与信号。选择假说的分子基础是B。在鼠感染过程中，伯氏螺旋体产生多种表型，如大量表达ospC的螺旋体和其他不表达ospC的螺旋体。OspC抗体选择性地消除表达ospC的表型，但允许不表达ospC的其它表型扩增。对于信令假设，B. burgdorferi能感应特异性抗体，并通过阻遏物的诱导选择性下调ospC。目的3是为了寻找选择假说的分子基础，或者排除在小鼠模型中抗体诱导的ospC下调中参与杀伤过程。公共卫生相关性：莱姆病由螺旋体细菌伯氏疏螺旋体引起，由鹿蜱传播，是北美和欧洲最常见的病媒传播疾病。仅在美国，每年就有超过20，000人感染这种疾病。莱姆病是一种多系统疾病，可导致关节炎、神经系统异常、心脏炎和皮肤病变，如游走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发展为后莱姆病综合征，这是一种无法治愈的神秘疾病。基因表达的严格调控是B致病策略的关键。burgdorferi。这项研究的目的是了解B。burgdorferi调节基因表达以满足其致病策略。