Discovery of Treponema pallidum antigens for development of a sensitive and specific diagnostic test for syphilis

尽管梅毒被认为是一种过去的疾病，但它仍然是一个严重的全球健康问题， 在世界各地的发展中国家和发达国家。在贫困地区，梅毒是一个重要的 死胎和新生儿死亡的原因是由于怀孕期间的垂直传播，而在发达国家， 在一些国家，它特别影响高危群体，如男男性行为者（MSM）。如果不治疗，梅毒 通常会导致严重的神经和心血管并发症，包括失明、耳聋、中风和 主动脉瓣狭窄需要一种更好和更简单的诊断测试来代替当前的两种测定诊断测试， 特别是如果可以区分早期诊断和疾病分期。一个实用的蛋白质组规模的平台， 抗体谱分析以前从未被梅毒研究界使用过，这项技术已经 快速发现新的生物标志物和改进梅毒诊断方法的能力。抗原 探索公司(ADI)将开发一个梅毒螺旋体梅毒亚种（TP）泛蛋白质组 微阵列检测纵向收集的兔血清中特异性抗TP IgG和IgM抗体水平 实验感染梅毒剂和患者血清。为此，ADI将与两家知名的 梅毒研究人员洛伦佐·贾卡尼博士是华盛顿大学的梅毒研究专家， 兔子梅毒模型，以及加州大学洛杉矶分校的杰弗里·克劳斯纳博士，他以梅毒流行病学而闻名。 在秘鲁利马的男男性接触者和变性妇女中进行的研究。泛蛋白质组阵列将包括多达1,000个梅毒 代表目前全球流行的两组现代梅毒菌株的蛋白质。我们假设 某些抗TP抗体可以作为生物标志物来检测早期感染或重复感染，以及 不同的疾病阶段。最有希望的诊断候选者将在兔子模型中确定， 对感染、治疗和再感染后的样本采集时间进行精确控制。随后，委员会注意到， 最佳候选人将通过测试来自秘鲁不同阶段的患者的血清来证实。 疾病我们期望鉴定出几种被抗体识别的TP蛋白，其中一些很快就会出现。 感染后，有些与疾病的阶段有关。未来的研究将验证诊断标志物 并开发一种原型诊断测试，可以测试FDA 510（k）许可。本申请涉及 简化和改进梅毒诊断方法的必要性，并选择通过 ADI公司掌握的创新蛋白质组学技术的应用。如果成功，我们的奋进将提供新的 工具和知识，以帮助遏制这种严重感染的蔓延。

In spite of being perceived as a disease of the past, syphilis remains a serious global health problem, affecting millions worldwide in both developing and developed countries. In underprivileged setting, syphilis is a significant cause of stillbirth and neonatal mortality due to vertical transmission during pregnancy, while in developed countries, it affects particularly high risk groups such as men who have sex with men (MSM). If untreated, syphilis often results in serious neurological and cardiovascular complications, including blindness, deafness, stroke and aortic aneurism. A better and simpler diagnostic test is desired to replace the current two-assay diagnostic tests, especially if early diagnosis and disease staging can be distinguished. A practical proteome-scale platform for antibody profiling has never before been available to the syphilis research community, and this technology has the power to rapidly discovery novel biomarkers and improve syphilis diagnostics approaches. Antigen Discovery, Inc. (ADI) of Irvine, CA, will develop a Treponema pallidum subspecies pallidum (TP) panproteome microarray to measure specific anti-TP IgG and IgM antibody levels in longitudinally collected sera from rabbits experimentally infected with syphilis agents and in patient sera. To this end, ADI will partner with two established syphilis investigators, Dr. Lorenzo Giacani, based at the University of Washington and expert in the use of the rabbit model of syphilis, and Dr. Jeffrey Klausner, based at UCLA, renowned for his syphilis epidemiological studies in MSM and transgender women in Lima, Peru.The panproteome array will include up to 1,000 syphilis proteins representing two groups of modern syphilis strains currently circulating globally. We hypothesize that certain anti-TP antibodies can serve as biomarkers to detect early infections or repeat infections, as well as different disease stages. The most promising diagnostic candidates will be identified in the rabbit model, which has exquisite control over the timing of sample collection after infection, treatment and reinfection. Subsequently, the top candidates will be confirmed in humans by testing the sera from Peruvian patients with varying stages of disease. We expect to identify several TP proteins that are recognized by antibodies, some which appear soon after infection and some that correlate with the stage of disease. Future studies will validate diagnostic markers and develop a prototype diagnostic test that can be tested for FDA 510(k) clearance. This application addresses the necessity of simplifying and improving syphilis diagnostics approaches, and choses to do it through the application of an innovative proteomic technology mastered by ADI. If successful, our endeavor will provide new tools and knowledge to help stem the spread of this serious infection.