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，一种由梅毒螺旋体亚种引起的性传播感染。苍白球（TPA）