Global sequence and surface antigenic diversity of Treponema pallidum outer membrane proteins

项目摘要 梅毒是一种由梅毒螺旋体（TPA）引起的多阶段性传播疾病， 仍然是一个重大的全球公共卫生问题。尽管抗体（Ab）的广泛可用性- 基于筛查测试和有效的抗菌治疗，梅毒控制策略已经满足了许多需求， 挑战，特别是在资源贫乏的国家，适当的诊断和伙伴服务， 传输并不总是可行的。传统的公共卫生预防策略无法 遏制性病梅毒的传播强调迫切需要开发一种安全有效的疫苗 覆盖全球目前的提案（U19- CRC项目2）体现了一种新的翻译 这种方法将大大有助于梅毒疫苗的开发， 了解梅毒螺旋体的基本膜和分子生物学（U19 CRC项目 1)和反向疫苗学方法，可以询问抗体（Ab）反应的细菌elevant 在其人类宿主中，TPA外膜（OMP）靶点是不同的和独特的。我们认为， 在全球范围内，TPA OMP抗原靶标及其变体的表征将使我们 梅毒疫苗原，其诱导调理素抗体和保护的能力可以被测试（目的1，2 和3）。我们的微生物、免疫学和翻译学的两项主要进展 研究让我们能够检验我们的统一假设。第一，我们取得了重大进展 表征TPA的罕见OMP的剧目（U19 CRC项目1），第二，我们已经做出了完善的 现有的和开发的新方法来评估患者中调理素抗OMP抗体的存在 血清以及这些靶标中的抗原多样性如何影响它们识别循环TPA的能力（项目 2和3）。总的来说，我们在美国、哥伦比亚、马拉维和中国的梅毒临床网络， 由内科科学家、流行病学家、免疫学家和微生物学家组成的专家组指导， 基因组学和分析专家，为招募和研究早期梅毒患者奠定必要的基础 在全球范围内（目标1），收集和提取TPA DNA，以了解OMP的完整分类 通过循环TPA（Aim 2）全面表达，并了解梅毒抗体是否确实能够 识别候选疫苗抗原及其抗原变体（目的3）。最后，我们的方法 将有助于配制和测试候选TPA OMP抗原并模拟这种疫苗的作用 可以在全球范围内使用。

PROJECT SUMMARY ABSTRACT Syphilis, a multi-stage sexually transmitted disease caused by the spirochete Treponema pallidum (TPA), continues to be a major worldwide public health problem. Despite the wide availability of antibody (Ab)- based screening tests and effective antimicrobial therapy, syphilis control strategies have met many challenges, particularly in resource-poor countries where proper diagnosis and partner services to reduce transmission are not always feasible. The inability of traditional public health prevention strategies to curtail the spread of venereal syphilis underscores the critical need to develop a safe and effective vaccine that has global coverage. The current proposal (U19- CRC Project 2) embodies a novel translational approach that will greatly contribute towards syphilis vaccine development that builds upon our extensive understanding of the basic membrane and molecular biology of the syphilis spirochete (U19 CRC Project 1) and reverse vaccinology methods that can interrogate the antibody (Ab) responses the bacterium elicits in its human host to distinct and unique TPA outer membrane (OMP) targets. It is our contention that the characterization of TPA OMP antigenic targets and their variants, on a global scale, will lead us to syphilis vaccinogens whose ability to induce opsonic antibodies and protection can be tested (Aims 1, 2 and 3). Two major developments stemming from our microbiologic, immunologic and translational studies position us to test our unifying hypothesis. First, we have made significant progress characterizing TPA's repertoire of rare OMPs (U19 CRC Project 1) and second, we have made refined existing and developed new methods to assess the presence of opsonic anti-OMP antibodies in patient sera and how antigenic diversity in these targets affects their ability to recognize circulating TPA (Project 2 and 3). Collectively, our syphilis clinical network in the United States, Colombia, Malawi and China, steered by an expert group of physician scientists, epidemiologists, immunologists and microbiologists, genomics and analytics experts, lay the necessary groundwork to enroll and study early syphilis patients at a global scale (Aim 1), collect and extract TPA DNA to understand the complete assortment of OMPs that are expressed globally by circulating TPA (Aim 2), and understand if syphilitic Abs are indeed able to recognize candidate vaccine antigens and their antigenic variants (Aim 3). In the end, our approach will lend itself to formulate and test candidate TPA OMP antigens and model the effects of such a vaccine that can be used globally.