OspC regulation and pathogenic strategy of Borrelia burgdorferi

描述(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病媒传播疾病。其表面脂蛋白抗原的协调表达对其致病策略至关重要。伯氏杆菌在充血和扁平的硬蜱体内大量产生外表面蛋白A(OspA)，但下调OspA并上调OspC对血餐的反应。OspC的表达最终会引起强烈的体液反应，给病原体带来巨大的压力。为了逃避保护性免疫，伯氏杆菌下调了OspC的表达。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操纵子的参与，并假设伯氏杆菌通过操纵子与未知调节蛋白的相互作用下调OspC和OspA。该项目首先将重点放在这些监管机构上。体外系统将被用来识别目标1中的这些调节因子；在目标2中，将在动物模型中研究它们归因于伯氏杆菌逃避免疫系统并导致持续感染的能力的基本作用。该项目将进一步扩大，以探索调控SPC下调的机制。为了实现这一目标，我们概述了两个假设：选择与信号传递。选择假说的分子基础是伯氏杆菌在小鼠感染过程中产生多种表型，例如大量表达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，但允许其他不表达OspC的表型扩大。对于信号假说，伯氏杆菌可以感知特异性抗体，并通过诱导抑制物选择性地下调OspC。目的3要么是为了寻找选择假说的分子基础，要么是为了排除抗体诱导的OspC下调在小鼠模型中参与的杀伤过程。公共卫生相关性：由伯氏疏螺旋体细菌引起的莱姆病是北美和欧洲最常见的媒介传播疾病，该细菌由鹿虱传播。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、心脏炎和皮肤损害，如红斑迁徙和慢性萎缩性肢端皮炎。如果不治疗，这种感染和疾病可能会持续数年。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征，这是一种无法治愈的神秘疾病。严密的基因表达调控是伯氏杆菌致病策略的关键。这项拟议的研究的目标是了解伯氏杆菌如何调节基因表达以满足其致病策略。

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.