Mechanisms of Mycobacterial Antigen Processing

分枝杆菌抗原加工机制

• 批准号: 7879289
• 负责人: Chinnaswamy Jagannath
• 金额: $ 44.5万
• 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/7879289
• 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; Immune response; Immune system; Immunity; Individual; Infection; Infection prevention; Investigation; Knowledge; Lead; Lysosomes; Mediating; Meningeal 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; public health relevance; response; 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）：结核病是对人类产生巨大影响的全球疾病。每年死于结核病的人比其他疾病多。可用的BCG疫苗对儿童具有部分保护作用，对成人疾病无效。我们已经确定，有助于降低BCG疫苗功效的一个主要因素是它可以防止巨噬细胞中有效的抗原加工的能力。我们还发现，来自结核分枝杆菌（？FBPA）的突变疫苗比BCG更好地保护小鼠。因此，这项研究将使用该候选疫苗，并检验以下假设：树突状细胞中改善的“肽抗原加工”将为开发针对结核病的更有效的疫苗铺平道路。由于吞噬体的成熟停滞，BCG疫苗的结构抗原在吞噬体中保持隔离，而其分泌的抗原的MHC-II和MHC-I肽表位对其分泌的抗原进行了最小处理。相反，FBPA新型疫苗经历了有限的吞噬体成熟，对MHC-II途径的肽呈现增强，我们假设它也通过MHC-I机制呈现肽。与当前使用的BCG疫苗不同，FBPA具有完整的ESAT-6和CFP-10蛋白质，我们将通过选择性删除基因的选择性删除以及ESAT-6，AG85B和CFP-10抗原的过度表达来通过修饰病原体成分​​来增强抗原性。因此，我们将确定引起与疫苗设计相关的保护性免疫反应的病原体成分​​，并通过具有增加的免疫原性和安全性来制备新型疫苗构建体。该提案的主要目的是开发一种吞噬体成熟的？FBPA疫苗的衍生品，预计将被树突状细胞更有效地处理，以比以前的疫苗更有效地呈现更多的免疫原性肽。目的是 - i）研究通过增强MHC-II肽的表现来提高？FBPA候选疫苗的免疫原性的细胞内策略，ii）ii）表征了MHC-I肽的特征，从而增加了FBPA候选疫苗的免疫原性。公共卫生相关性：结核病是由于细菌感染和通过疫苗预防这种疾病的主要死亡原因，将对人类的公共卫生和未来产生影响。艾滋病和结核病是撒哈拉以南非洲和亚洲的致命组合，也需要努力来开发多价疫苗。该建议也解决了这个问题。这是一项研究赠款提案，旨在使用野生型结核分枝杆菌的遗传操纵开发新的结核病疫苗。缺乏AG85A（？FBPA）的初始候选疫苗已经生产出来，该疫苗由于其具有有限的吞噬体成熟的性质，从而显示出有希望的疫苗功效，从而增强了抗原呈递。高度免疫原性疫苗可以用作多种载体疫苗，并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，涉及休斯顿大学希思科学中心（Jagannath博士和亨特博士）希思科学中心 - 桑·安东尼奥（Dhandayuthapani博士）和俄克拉荷马大学（William Hildebrand博士）。这些团队将以高度协同的方式进行疫苗评估，遗传重建和表位发现，并提高我们对抗结核疫苗的现有知识。