Six new Chlamydia epitopes

六个新的衣原体表位

• 批准号: 8280847
• 负责人: RAYMOND Morris JOHNSON
• 金额: $ 19.45万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280847
• 关键词: Address; Adolescent; Amino Acids; Antibiotic Therapy; Antibodies; Antigens; Applications Grants; Bacteria; Bacterial Sexually Transmitted Diseases; Binding; Biology; CD4 Positive T Lymphocytes; Cell Line; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Cicatrix; Consensus; Data; Dendritic Cells; Development; Disease; Ectopic Pregnancy; Epithelial; Epithelial Cells; Epithelium; Epitopes; Escherichia coli; Future; Genetic Recombination; Genital system; Genome; Genomics; Goals; Human; Immune response; Immunity; In Vitro; Incidence; Infection; Infertility; Investigation; Libraries; MHC Class II Genes; Maps; Mediating; Modeling; Mus; Mutagenesis; Pathway interactions; Peptides; Play; Prevalence; Process; Proteins; Public Health; Publishing; Recombinants; Relative (related person); Research; Research Personnel; Role; Source; Subunit Vaccines; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Tubal Pregnancy; Vaccinated; Vaccine Antigen; Vaccines; Western Europe; Whole Organism; Woman; antigen processing; base; immunogenic; immunogenicity; immunopathology; in vivo; interest; major outer membrane protein; mouse model; mutant; novel; reproductive; research study; tool; trachoma vaccine; trait; vaccine candidate; vaccine development; young adult

DESCRIPTION (provided by applicant): Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the developed world with a prevalence approaching 10% in adolescents and young adults. In women C. trachomatis infections ascend into the upper reproductive tract causing scarring that results in infertility and ectopic pregnancy. Antibiotic therapy has been ineffective in addressing the prevalence of the disease making development of a protective vaccine a logical approach to address this common infection. Existing data from the C. muridarum mouse model shows a correlation between a CD4 T cell clones ability to control replication of Chlamydia in epithelial cells in vitro and its ability to protect the reproductive tract in vivo. Similarly, existing vaccine data in the C. muridarum model has shown that not all Chlamydia antigens induce protective immunity. The major challenge for development of a protective Chlamydia vaccine is identifying which of the ~900 Chlamydia proteins is capable of inducing protective immunity. We hypothesize based on existing data that the protective epitopes will be found in the subset of Chlamydia proteins that are processed and presented by infected epithelial cells, generating a CD4 T cell response capable of controlling Chlamydia replication in epithelial cells. CD4 T cell clones that recognize and control C. muridarum replication in epithelial cells are logical tools for identifying candidate vaccine antigens. We propose using our unique epithelial cell lines, existing panel of Chlamdydia- specific CD4 T cell clones, and novel technologic expertise in generating Chlamydia mutants and recombinants to accomplish the following specific aims: #1 to identify six new "epithelial" CD4 epitope-source proteins using recombinant and mutant libraries of C. muridarum combined with genomic sequencing, #2 to investigate the role of epitope abundance on infected epithelial cells as a parameter for CD4 T cell-mediated control of C. muridarum replication in epithelial cells, #3 to investigate the ability of each identified epitope source protein to induce protective vaccine immunity in the C. muridarum mouse model. PUBLIC HEALTH RELEVANCE: Research outlined in this grant proposal will help define the specific proteins included in a future Chlamydia vaccine. Such a vaccine would reduce Chlamydia infections and their complications including infertility and potentially fatal tubal pregnancies.

描述（由申请人提供）：沙眼衣原体是发达国家最常见的细菌性性传播疾病，在青少年和年轻人中的患病率接近 10%。在女性中，沙眼衣原体感染上升到上生殖道，造成疤痕，导致不孕和宫外孕。抗生素疗法在解决该疾病的流行方面无效，因此开发保护性疫苗成为解决这种常见感染的合理方法。来自 C. muridarum 小鼠模型的现有数据显示，CD4 T 细胞克隆在体外控制上皮细胞中衣原体复制的能力与其在体内保护生殖道的能力之间存在相关性。同样，鼠衣原体模型中的现有疫苗数据表明，并非所有衣原体抗原都能诱导保护性免疫。开发保护性衣原体疫苗的主要挑战是确定约 900 种衣原体蛋白中的哪一种能够诱导保护性免疫。我们根据现有数据假设，保护性表位将存在于由受感染的上皮细胞加工和呈递的衣原体蛋白子集中，产生能够控制上皮细胞中衣原体复制的 CD4 T 细胞反应。识别和控制上皮细胞中鼠棒状杆菌复制的 CD4 T 细胞克隆是识别候选疫苗抗原的合理工具。我们建议利用我们独特的上皮细胞系、现有的衣原体特异性 CD4 T 细胞克隆组以及生成衣原体突变体和重组体的新颖技术专长来实现以下具体目标：#1 使用鼠衣原体重组和突变文库结合基因组测序来鉴定六种新的“上皮”CD4 表位来源蛋白，#2 研究其作用 感染上皮细胞上的表位丰度作为 CD4 T 细胞介导的控制上皮细胞中 C. muridarum 复制的参数，#3 研究每个已识别表位源蛋白诱导保护性的能力 C. muridarum 小鼠模型中的疫苗免疫。 公共卫生相关性：本拨款提案中概述的研究将有助于确定未来衣原体疫苗中包含的特定蛋白质。这种疫苗将减少衣原体感染及其并发症，包括不孕症和可能致命的输卵管妊娠。