Proteome-wide cellular immunity approach to P. falciparum antigen identification

用于恶性疟原虫抗原鉴定的蛋白质组细胞免疫方法

• 批准号: 8302969
• 负责人: Denise L. Doolan
• 金额: $ 59.76万
• 依托单位: QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302969
• 关键词: Adenoviruses; Affinity; Algorithms; Alleles; Amino Acid Sequence; Antigen Targeting; Antigens; Binding; Bioinformatics; Biological Assay; Blast Cell; CD4 Positive T Lymphocytes; CD8B1 gene; Cellular Assay; Cellular Immunity; Data; Data Set; Databases; Elements; Epitopes; Erythrocytes; Ethnic Origin; Exposure to; Gene Expression Profile; Genes; Genetic; Genome; Genomics; HLA-A1 Antigen; HLA-A3 Antigen; HLA-DR Antigens; Human; Immune; Immune response; Immunity; Immunodominant Antigens; Immunodominant Epitopes; In Vitro; Individual; Infection; Interferons; Life Cycle Stages; MHC Class I Genes; MHC binding peptide; Malaria Vaccines; Mining; Mus; Open Reading Frames; Orthologous Gene; Outcome; Parasites; Peptides; Peripheral Blood Mononuclear Cell; Plasmodium; Plasmodium falciparum; Population; Poxviridae; Proteins; Proteome; Proteomics; Recombinants; Regimen; Research; Scanning; Screening procedure; Solutions; Sporozoites; Staging; Sterility; Subunit Vaccines; T-Lymphocyte Epitopes; Testing; Vaccines; Variant; base; cross reactivity; design; efficacy evaluation; novel; novel strategies; transcriptomics; vaccine development

DESCRIPTION (provided by applicant): The long-term objective of this project is to identify and prioritize for malaria vaccine development novel P. falciparum antigens and epitopes that are recognized by individuals exposed to P. falciparum in the context of multiple genetic restrictions, by mining the P. falciparum genomic sequence. The feasibility of a malaria vaccine is supported by experimental data demonstrating that protective immunity can be induced by exposure to intact Plasmodium parasites. The antigenic targets of this protection have not been identified. P. falciparum expresses an estimated 5,300 proteins, each of which is a potential target of protective immune responses. Although the P. falciparum genome, proteome, and transcriptome have now been elucidated, it has not been obvious how to use this information for vaccine development. The current application offers a solution to this problem, by applying an integrated approach that incorporates bioinformatic predictions, HLA supertype considerations, high-throughput MHC peptide binding assays, and cellular assays. The specific aims are to: (1) identify, from the complete set of approximately 2500 genes expressed in the pre-erythrocytic stage of the P. falciparum parasite life cycle, those proteins that correspond to immunodominant antigens recognized in the context of multiple genetic restrictions by individuals exposed to P. falciparum; (2) for a subset of the100 most immunodominant antigens, identify the CD8+ and CD4+ T epitopes that are the targets of P. falciparum parasite-induced immunity, and their associated HLA Class I and II restriction elements; (3) for 50 antigens, characterize five epitopes/antigen for extent of sequence conservation or immunological cross-reactivity between different Plasmodium strains; and (4) for 10 antigens, evaluate the capacity to protect against Plasmodium sporozoite challenge in mice. It is expected that the proposed research will result in the identification of novel P. falciparum antigens that will represent good candidates for a vaccine that would be effective in all ethnicities. Additionally, data will demonstrate whether protective immune responses are targeted against only a few immunodominant antigens, or are broadly distributed against a large range of antigens, and will therefore provide valuable information regarding the potential multivalency of candidate malaria vaccines. It is expected that the proposed research will have important outcomes for malaria vaccine development. It will identify novel P. falciparum antigens that should represent good candidates for a subunit malaria vaccine that would be effective in all human populations regardless of ethnicity. Additionally, data will demonstrate whether protective immune responses are targeted against only a few immunodominant antigens, or are broadly distributed against a large range of antigens, and will therefore provide valuable information regarding the potential multivalency of candidate malaria vaccines.

描述（由申请人提供）：该项目的长期目标是通过挖掘恶性疟原虫基因组序列，识别并优先开发疟疾疫苗开发新的恶性疟原虫抗原和表位，这些抗原和表位是在多种遗传限制的情况下暴露于恶性疟原虫的个体所识别的。实验数据证明了疟疾疫苗的可行性，表明接触完整的疟原虫寄生虫可以诱导保护性免疫力。这种保护的抗原靶标尚未确定。恶性疟原虫大约表达 5,300 种蛋白质，其中每一种都是保护性免疫反应的潜在目标。尽管恶性疟原虫基因组、蛋白质组和转录组现已阐明，但如何利用这些信息进行疫苗开发尚不清楚。当前的应用程序通过应用综合方法来解决这个问题，该方法结合了生物信息学预测、HLA超型考虑、高通量MHC肽结合测定和细胞测定。具体目标是：（1）从恶性疟原虫生命周期红细胞前阶段表达的约2500个基因的完整集合中，鉴定出那些与暴露于恶性疟原虫的个体在多重遗传限制的背景下识别的免疫显性抗原相对应的蛋白质； (2) 对于 100 个最具免疫优势的抗原的子集，鉴定作为恶性疟原虫寄生虫诱导免疫的目标的 CD8+ 和 CD4+ T 表位，及其相关的 HLA I 类和 II 类限制元件； (3) 对于 50 种抗原，表征不同疟原虫菌株之间的序列保守程度或免疫交叉反应性的 5 个表位/抗原； (4) 对于 10 种抗原，评估小鼠抵抗疟原虫子孢子攻击的能力。预计拟议的研究将鉴定出新型恶性疟原虫抗原，这些抗原将成为对所有种族都有效的疫苗的良好候选者。此外，数据将证明保护性免疫反应是否仅针对少数免疫显性抗原，或者广泛分布于针对多种抗原，因此将提供有关候选疟疾疫苗的潜在多价性的有价值的信息。预计拟议的研究将为疟疾疫苗的开发产生重要成果。它将鉴定出新的恶性疟原虫抗原，这些抗原应该代表亚单位疟疾疫苗的良好候选者，该疫苗对所有人群（无论种族）都有效。此外，数据将证明保护性免疫反应是否仅针对少数免疫显性抗原，或者广泛分布于针对多种抗原，因此将提供有关候选疟疾疫苗的潜在多价性的有价值的信息。