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

梅毒螺旋体外膜蛋白的整体序列和表面抗原多样性

• 批准号: 10399447
• 负责人: Juan C Salazar
• 金额: $ 62.53万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399447
• 关键词: Affect; Africa South of the Sahara; Amino Acid Substitution; Antibodies; Antibody Response; Antibody-mediated protection; Antigenic Diversity; Antigenic Variation; Antigens; Appearance; Automobile Driving; B-Lymphocyte Epitopes; Bacteria; Catalogs; China; Clinical; Clinical Research; Colombia; Consensus; Country; Coupled; DNA; Developed Countries; Development; Diagnosis; Disease; Enrollment; Epidemic; Epidemiologist; Epitopes; Evolution; Genomics; Globus Pallidus; Human; IgG1; Immunodominant Epitopes; Immunoglobulin M; Immunologics; Immunologist; Individual; Infection; Inflammatory; Latent Syphilis; Lead; Location; Low Birth Weight Infant; Malawi; Mediating; Membrane; Membrane Biology; Membrane Proteins; Methods; Microbiology; Mind; Modeling; Molecular Biology; Natural History; North America; Order Spirochaetales; Organ; Organism; Oryctolagus cuniculus; Patients; Peritoneal; Persons; Phase; Physicians; Population; Positioning Attribute; Pregnancy; Pregnant Women; Prevalence; Prevention strategy; Proteins; Public Health; Resources; Scientist; Services; Sexually Transmitted Diseases; Signs and Symptoms; Site; South America; Structural Models; Structure; Surface; Surveys; Syphilis; Testing; Time; Tissues; Treatment Protocols; Treponema pallidum; United States; Vaccine Antigen; Vaccines; Variant; adverse outcome; antimicrobial; base; effective therapy; experimental study; extracellular; macrophage; men who have sex with men; monocyte; novel; novel strategies; offspring; pathogen; pathogenic bacteria; premature; screening; skin lesion; stem; stillbirth; syphilis vaccine; translational approach; translational study; transmission process; vaccine candidate; vaccine development; vaccinology

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.

项目总结摘要 梅毒是一种由梅毒螺旋体(TPA)引起的多阶段性传播疾病， 仍然是一个重大的世界性公共卫生问题。尽管抗体(Ab)广泛可用，但- 基于筛查测试和有效的抗微生物治疗，梅毒控制策略已经遇到了许多 挑战，特别是在资源贫乏的国家，在这些国家，适当的诊断和伙伴服务需要减少 传播并不总是可行的。传统的公共卫生预防战略无法 遏制性病梅毒的传播强调了开发安全有效的疫苗的迫切需要 它覆盖了全球。目前的提案(U19-CRC项目2)体现了一种新的翻译 这一方法将极大地促进梅毒疫苗的开发，该疫苗建立在我们广泛的 对梅毒螺旋体基础膜和分子生物学的认识(U19 CRC项目 1)和反向疫苗学方法，可以询问细菌引起的抗体(Ab)反应 在其人类宿主中具有独特的TPA外膜(OMP)靶标。我们的论点是 在全球范围内，对TPA OMP抗原靶及其变体的表征将引导我们 梅毒疫苗原，其诱发抗体和保护的能力可被测试(目标1、2 和3)。来自我们的微生物学、免疫学和转化学的两个主要发展 研究使我们能够检验我们统一的假设。一是取得重大进展。 描述TPA的稀有OMP曲目(U19 CRC项目1)；第二，我们已精炼 现有和开发的新方法来评估患者中是否存在光学抗OMP抗体 血清以及这些靶点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， 在一个由内科科学家、流行病学家、免疫学家和微生物学家组成的专家组的指导下， 基因组学和分析专家为招募和研究早期梅毒患者奠定了必要的基础 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全球表达(目标2)，并了解梅毒抗体是否真的能够 识别候选疫苗抗原及其抗原变体(目标3)。最后，我们的方法 将有助于研制和测试候选的TPA OMP抗原，并模拟这种疫苗的效果 这可以在全球范围内使用。