A serologic assay to measure successful Lyme borreliosis antibiotic therapy

描述(申请人提供)：莱姆病，由于感染硬蜱传播的伯氏疏螺旋体螺旋体，是美国最常见的媒介传播疾病，每年向疾控中心报告超过20,000例。对于实现莱姆病临床治愈所必需的抗生素治疗的持续时间存在争议。检测伯氏杆菌抗体的血清学测试(ELISA和免疫印迹)是目前莱姆病最敏感和最广泛使用的实验室测试，但它们不评估对治疗的反应，也不能区分既往接触伯氏杆菌和活动性感染。确定在抗生素治疗后实验室治愈的时间仍然是一个巨大的、尚未得到满足的医学需要，以区分急性感染或再感染与以前的接触，并防止使用长期抗生素进行不必要的治疗。为了满足这一需求，我们评估了莱姆疏螺旋体病小鼠模型的抗生素治疗。我们发现，在成功的抗生素治疗后，对疏螺旋体的一部分抗原的免疫球蛋白应答迅速下降。这项第一阶段的提案旨在通过蛋白质组学方法改进目前可用的莱姆病血清学测试，该方法将a)确定成功的抗生素治疗后小鼠抗体反应下降的伯氏杆菌抗原，以及b)评估它们在区分活动性感染和用抗生素治愈的感染方面的诊断潜力。滴度的下降或对抗原的反应性的丧失将与抗生素灭菌相关，这将通过多种措施得到证实。候选诊断抗原将被生产为重组蛋白，并测试其与感染不同阶段使用抗生素治疗的小鼠的血清以及代表伯氏杆菌感染不同阶段的患者血清的反应性。这些诊断测试在患者身上的特异性和敏感性将在第二阶段确定，并将开发用于商业临床实验室的预测成功消除抗生素感染的定量ELISA法。 与公共卫生相关：莱姆病是一种由壁虱传播的伯氏疏螺旋体感染。一些人甚至在抗生素治疗后仍有挥之不去的症状，而且还没有测试来确定抗生素在消除感染方面的有效性。我们的目的是通过引入新的血清学测试来预测感染何时治愈并区分既往接触和活动性感染，从而显著改善对莱姆疏螺旋体病治疗患者的评估。

DESCRIPTION (provided by applicant): Lyme disease, due to infection with the Ixodes tick-transmitted spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States, with over 20,000 cases reported to the CDC annually. There is controversy over the length of antibiotic therapy that is necessary to achieve a clinical cure for Lyme disease. Serologic tests (ELISA and immunoblot) that detect antibodies against B. burgdorferi are currently the most sensitive and widely available laboratory tests for Lyme disease, but they do not assess response to therapy and can not distinguish previous exposure to B. burgdorferi from active infection. The determination of when a laboratory cure is achieved after antibiotic treatment remains a large, unmet medical need for distinguishing acute infection or re-infection from previous exposure and for preventing unnecessary treatment with long-term courses of antibiotics. To address this need, we have assessed antibiotic therapy in the mouse model of Lyme borreliosis. We found that IgG responses decline rapidly to a subset of Borrelia antigens after successful antibiotic therapy. This Phase I proposal seeks to improve upon the currently available serologic tests for Lyme disease through a proteomic approach that will a) identify the B. burgdorferi antigens to which murine antibody responses decline after successful antibiotic treatment and b) evaluate their diagnostic potential in distinguishing active infections from those cured with antibiotics. Declines in titer or loss of reactivity to the antigens will be correlated with antibiotic sterilization that will be confirmed by multiple measures. The candidate diagnostic antigens will be produced as recombinant proteins and tested for reactivity with sera from mice treated with antibiotics at different stages of infection and patient sera representative of various stages of B. burgdorferi infection. The specificity and sensitivity of these diagnostic tests in patients will be determined in Phase II, and quantitative ELISA assays that predict successful elimination of infection by antibiotics will be developed for use in commercial clinical laboratories. PUBLIC HEALTH RELEVANCE: Lyme disease is an infection with the tick-transmitted spirochete Borrelia burgdorferi. Some people have lingering symptoms even after antibiotic therapy, and there is no test to determine the effectiveness of antibiotics at eliminating the infection. Our intent is to significantly improve the evaluation of patients treated for Lyme borreliosis through the introduction of new serologic tests that predict when infection has been cured and distinguish prior exposure from active infection.