Outer Membrance Protein vaccinogens of Treponema pallium

梅毒螺旋体外膜蛋白疫苗原

• 批准号: 10618189
• 负责人: Justin D Radolf
• 金额: $ 90.97万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618189
• 关键词: Adopted; Algorithms; Antibodies; Antigens; Architecture; Bioinformatics; Biological Assay; C-terminal; Catalogs; Containment; Data; Disease; Epidemiology; Escherichia coli; Family; Formulation; Genetic; Genome; Genomics; Gram-Negative Bacteria; Human; Immune; Immune Evasion; Immune Sera; Immunization; Infection; Laboratories; Lipoproteins; Macrophage; Membrane; Membrane Proteins; Membrane Transport Proteins; Molecular; Molecular Chaperones; Molecular Machines; Mus; Order Spirochaetales; Oryctolagus cuniculus; Pathogenicity; Patients; Periplasmic Proteins; Population; Proteins; Research Personnel; Resistance; Serum; Sexually Transmitted Diseases; Societies; Structural Models; Surface; Surface Antigens; Syphilis; Testing; Translating; Treponema; Treponema pallidum; Treponema pallidum subspecies pallidum; United States; Vaccine Design; Vaccines; Vertical Disease Transmission; adverse pregnancy outcome; amphiphilicity; antigen test; biophysical analysis; cross immunity; falls; member; men; novel; paralogous gene; pathogen; physical property; sex; syphilis vaccine; vaccine candidate; vaccine development; vaccinology

Syphilis, a sexually transmitted infection caused by the Treponema pallidum subsp. pallidum (TPA), has undergone a dramatic resurgence in the United States since the late 1990s. Syphilis also poses a major threat globally with an estimated 5.6 million new cases annually and 350,000 adverse pregnancy outcomes due to mother-to-child transmission. There is a growing sense of urgency about the need for a syphilis vaccine as a cornerstone of a strategy for global containment. Our quest to develop a syphilis vaccine began with the recognition that the outer membrane (OM) of TPA differs fundamentally from those of prototypical Gram- negative bacteria, such as E. coli. We hypothesized that TPA's `unorthodox' OM is the basis for its impressive capacity for immune evasion and that identification of TPA's repertoire of rare OM-spanning proteins (OMPs) holds the key to vaccine development. The ability of all previously tested antigens to confer at best only limited protection suggests that a syphilis vaccine will require multiple components and, consequently, the need for a pipeline of candidate vaccinogens to identify the combination that provides the greatest breadth and degree of local and systemic protection. Despite the availability of genomic sequences, until recently, syphilologists were unable to catalog the spirochete's `OMPeome'. The breakthrough came by using bioinformatics, computational, and structural algorithms to mine the TPA genome for proteins predicted to form an amphiphilic b-barrel, the structural hallmark of OM-spanning proteins. With this approach, we identified 20 candidate OMPs in TPA, which fall into two `classes': Tprs and a group of unrelated (`non-Tpr') b-barrel-forming proteins. For several (TP0326/BamA and members of Tpr subfamily I), b-barrel formation and OM localization in TPA has been validated by rigorous experimentation, and their ability to elicit potent opsonic activity also has been demonstrated. Our proposal takes the notion of `opsonic target as protective antigen' in an unbiased and novel direction: leading candidate OMP vaccinogens are selected based on genomic sequences, bioinformatics, biophysical analysis, and structural modeling, rather than whether they are recognized by immune sera generated during infection. Our pipeline consists of OMPs from four `groups': BamA, subfamily I and II Tprs, and the FadLs. In Aim 1, we will refine our topological and structural models for leading candidates in the Tpr subfamilies and FadL groups. In Aim 2, we will assess whether high titer antisera against one or more candidate OMPs promote opsonophagocytosis of TPA (an ex vivo correlate of protection) using rabbit and mouse macrophages. In Aim 3, we will determine in rabbits, and in exploratory studies with mice, if immunization with one or more OMPs provides broad as well as strong protection following challenge with diverse strains of TPA.

梅毒，是由毛毛虫粒子亚种引起的性传播感染。 Pallidum（TPA），有 自1990年代后期以来，美国经历了戏剧性的复兴。梅毒也构成了重大威胁 在全球范围内，每年有560万例新病例，由于 母子传播。关于梅毒疫苗的需求越来越紧迫 全球遏制战略的基石。我们寻求开发梅毒疫苗的寻求始于 认识到TPA的外膜（OM）与原型革兰氏集的根本不同 阴性细菌，例如大肠杆菌。我们假设TPA的“非正统” OM是其令人印象深刻的基础 免疫逃避的能力以及鉴定TPA稀有OM跨蛋白（OMP）的曲目 拥有疫苗开发的关键。 所有先前测试的抗原充其最多只有有限保护的能力表明梅毒 疫苗将需要多个成分，因此，需要候选疫苗的管道到 确定提供最大程度和程度的本地和系统保护程度的组合。尽管 直到最近，基因组序列的可用性仍无法分类螺旋体 ```''。突破是通过使用生物信息学，计算和结构算法来开采的 预测将形成两亲h的蛋白质的TPA基因组，这是OM跨化的结构标志 蛋白质。通过这种方法，我们在TPA中确定了20个候选人，它们属于两个“类”：TPRS和一个 一组无关（“非TPR”）B桶形成蛋白。对于几个（TP0326/BAMA和TPR的成员） 亚家族i），通过严格的实验验证了TPA中的B桶形成和OM定位， 他们的引发有力的opsonic活动的能力也已得到证明。我们的建议采用 ``opsonic靶标作为保护抗原''朝着公正和新颖的方向：领先的候选疫苗毒素 根据基因组序列，生物信息学，生物物理分析和结构建模选择。 与感染过程中产生的免疫血清相比，它们是否被识别。我们的管道由OMP组成 来自四个“群体”：巴马，亚家族I和II TPR和FADLS。在AIM 1中，我们将完善我们的拓扑和 TPR亚家族和FADL组中领先候选人的结构模型。在AIM 2中，我们将评估是否 针对一个或多个候选人的高滴度抗血清促进了TPA的脑吞噬作用（ex Vivo 使用兔子和小鼠巨噬细胞的保护）。在AIM 3中，我们将在兔子和 使用小鼠的探索性研究，如果一个或多个OMP免疫可提供广泛而强大的 在TPA的各种菌株中挑战后的保护。