Mechanisms of Mycobacterial Antigen Processing

分枝杆菌抗原加工机制

• 批准号: 8115175
• 负责人: Chinnaswamy Jagannath
• 金额: $ 43.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115175
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Aerosols; Africa South of the Sahara; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antitubercular Agents; Applications Grants; Area; Asia; Attenuated; Attenuated Vaccines; Autophagocytosis; Bacterial Infections; Binding Proteins; CD8B1 gene; Cathepsins; Cause of Death; Child; Complex; Defect; Dendritic Cell Vaccine; Dendritic Cells; Development; Disease; Emergency Situation; Employee Strikes; Engineering; Enzymes; Epitopes; Fibronectins; Future; Gene Deletion; Generations; Genetic; Genetic Engineering; Geographic Locations; Goals; Health; Immune response; Immune system; Immunity; Individual; Infection; Infection prevention; Investigation; Knowledge; Lead; Lysosomes; Mediating; Meningeal Tuberculosis; Miliary Tuberculosis; Mining; Modification; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigen 85A; Nature; Oklahoma; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Phagosomes; Polyvalent Vaccine; Principal Investigator; Process; Proteins; Public Health; Research Personnel; Research Project Grants; Safety; Science; T-Lymphocyte; Time; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Universities; Vaccinated; Vaccine Design; Vaccines; Validation; Virulent; antigen processing; genetic manipulation; human disease; immunogenic; immunogenicity; improved; macrophage; man; multicatalytic endopeptidase complex; mutant; mycobacterial; novel; novel vaccines; pathogen; peptide I; prevent; programs; response; retinal S antigen peptide M; tuberculosis immunity; vaccination against tuberculosis; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): Tuberculosis is a global disease of immense impact on mankind. More people die of tuberculosis each year than due to other diseases. The available BCG vaccine is partially protective against children and is not effective against adult disease. We have determined that one major factor that contributes to the reduced efficacy of BCG vaccine is its ability to prevent effective antigen processing in macrophages. We also discovered that a mutant vaccine from Mycobacterium tuberculosis (?fbpA) protects mice better than BCG. This investigation will therefore use this candidate vaccine and test the hypothesis that improved 'peptide antigen processing' in dendritic cells will pave the way for development of a more effective vaccine against tuberculosis. Due to phagosome maturation arrest, structural antigens of BCG vaccine remain sequestered within phagosomes while its secreted antigens are minimally processed for MHC-II and MHC-I peptide epitopes. In contrast, ?fbpA novel vaccine undergoes limited phagosome maturation, with enhanced peptide presentation for MHC-II pathway and we hypothesize that it also presents peptides through MHC-I mechanism. Unlike the currently used BCG vaccine, ?fbpA has intact ESAT-6 and CFP-10 proteins and we will enhance antigenicity by modification of pathogen components through selective deletion of genes as well as over expression of ESAT-6, Ag85B and CFP-10 antigens. We will therefore identify pathogen components that elicit protective immune responses relevant to vaccine design and prepare novel vaccine constructs through genetic engineering with increased immunogenicity and safety. The major goal of this proposal is to develop a phagosome maturation competent derivative of ?fbpA vaccine that is expected to be more efficiently processed by dendritic cells to present more immunogenic peptides than previous vaccines. The aims are to- I) Investigate the intracellular strategies that increase the immunogenicity of ?fbpA candidate vaccine by enhancing the presentation of MHC-II peptides, and II) Characterize the MHC-I peptides that increase the immunogenicity of ?fbpA candidate vaccine. PUBLIC HEALTH RELEVANCE: Tuberculosis is the leading cause of death due to bacterial infections and prevention of this disease through a vaccine will have an impact on the public health and future of mankind. AIDS and tuberculosis is a deadly combination in sub saharan Africa and Asia and efforts are also needed to develop polyvalent vaccines. This proposal addresses this issue as well. This is a research grant proposal that seeks to develop a new vaccine for tuberculosis using genetic manipulations of the wild type Mycobacterium tuberculosis. An initial candidate vaccine that lacks Ag85A (?fbpA) has already been produced that shows promising vaccine efficacy due to its nature of limited phagosome maturation leading to enhanced antigen presentation. The highly immunogenic vaccine can be potentially used as a polyvalent carrier vaccine and in a safer form for multiple diseases of the human disease. The project is a collaborative proposal which involves investigators at the University of Heath Sciences Center Houston (Dr. Jagannath and Dr. Hunter) University of Heath Sciences Center-San Antonio (Dr. Dhandayuthapani) and University of Oklahoma (Dr. William Hildebrand). The teams will perform vaccine evaluation, genetic re-construction and epitope discovery in a highly synergistic manner and boost our existing knowledge on anti-tuberculosis vaccines.

描述（由申请人提供）：结核病是一种对人类影响巨大的全球性疾病。每年死于结核病的人数多于死于其他疾病的人数。现有的卡介苗疫苗对儿童具有部分保护作用，但对成人疾病无效。我们已经确定，导致卡介苗疫苗功效降低的一个主要因素是其阻止巨噬细胞有效抗原加工的能力。我们还发现，结核分枝杆菌 (?fbpA) 突变疫苗比卡介苗能更好地保护小鼠。因此，这项研究将使用这种候选疫苗并测试以下假设：改善树突状细胞中的“肽抗原处理”将为开发更有效的结核病疫苗铺平道路。由于吞噬体成熟停滞，BCG 疫苗的结构抗原仍被隔离在吞噬体内，而其分泌的抗原被最低程度地加工为 MHC-II 和 MHC-I 肽表位。相比之下，?fbpA新型疫苗经历了有限的吞噬体成熟，增强了MHC-II途径的肽呈递，我们假设它也通过MHC-I机制呈递肽。与目前使用的卡介苗疫苗不同，?fbpA具有完整的ESAT-6和CFP-10蛋白，我们将通过选择性删除基因以及过度表达ESAT-6、Ag85B和CFP-10抗原来修饰病原体成分​​，从而增强抗原性。因此，我们将识别引起与疫苗设计相关的保护性免疫反应的病原体成分​​，并通过基因工程制备具有更高免疫原性和安全性的新型疫苗结构。该提案的主要目标是开发一种具有吞噬体成熟能力的 ?fbpA 疫苗衍生物，预计该衍生物可以被树突状细胞更有效地加工，从而比以前的疫苗呈现更多的免疫原性肽。目的是- I) 研究通过增强 MHC-II 肽的呈递来增加 ?fbpA 候选疫苗免疫原性的细胞内策略，以及 II) 表征增加 ?fbpA 候选疫苗免疫原性的 MHC-I 肽。公共卫生相关性：结核病是细菌感染导致死亡的主要原因，通过疫苗预防这种疾病将对公共卫生和人类的未来产生影响。艾滋病和结核病在撒哈拉以南非洲和亚洲是致命的组合，还需要努力开发多价疫苗。该提案也解决了这个问题。这是一项研究拨款提案，旨在利用野生型结核分枝杆菌的基因操作来开发一种新的结核病疫苗。缺乏 Ag85A (?fbpA) 的初始候选疫苗已经生产出来，由于其有限的吞噬体成熟导致抗原呈递增强的性质，该疫苗显示出有希望的疫苗功效。该高免疫原性疫苗可潜在地用作多价载体疫苗，并且以更安全的形式用于人类疾病的多种疾病。该项目是一项合作提案，涉及休斯顿健康科学中心大学（Jagannath 博士和 Hunter 博士）、圣安东尼奥健康科学中心大学（Dhandayuthapani 博士）和俄克拉荷马大学（William Hildebrand 博士）的研究人员。这些团队将以高度协同的方式进行疫苗评估、基因重建和表位发现，并增强我们在抗结核疫苗方面的现有知识。