Immunobiology of Bacillus anthracis Spore-Host Interactions

炭疽芽孢杆菌孢子-宿主相互作用的免疫生物学

基本信息

批准号：
7914409
负责人：
John Franklin Kearney
金额：
$ 36.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914409
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Affect Animals Anthrax disease Antibiotics Antibodies Bacillus anthracis Bacillus anthracis spore Bacteria Biochemical Cell Communication Cell Line Cell-Matrix Junction Cells Cessation of life Data Dendritic Cells Development Disease Elements Engineering Environment Epitopes FOS gene Fc Receptor Gastrointestinal tract structure Gene Targeting Genes Germination Goals Human Immune Immune response Immunity Immunobiology Immunoglobulin Isotypes In Vitro Infection Inflammatory Influentials Ingestion Interleukin-12 Intervention Lead Ligands Macrophage Activation Macrophage-1 Antigen Mediating Methods Military Personnel Mus Mutant Strains Mice Mutate NF-kappa B Nature Organism Outcome PI3K/AKT Pathway interactions Phagocytes Phagocytosis Pharmaceutical Preparations Play Process Production Proteins Publishing Receptor Cell Regimen Reproduction spores Resistance Role Septic Toxemia Septicemia Signal Pathway Skin Staging Surface Terrorism Testing Therapeutic Toxin Transcription Factor AP-1 Vaccines Virulence base cell type cytokine enhancing factor in vivo in vivo Model interest killings long term memory macrophage pathogen prevent public health relevance receptor response uptake

项目摘要

DESCRIPTION (provided by applicant): The use of Bacillus anthracis as a bioweapon depends on dispersal of its spores in the environment, entrance into the body, spore uptake by the human host cells, germination of the spores in the host and the pathological consequences of the host response to the toxins elaborated by the vegetative cells within the host. Very little is known of the mechanisms of spore entry into the host, including the nature of targeted cell types in the airways, digestive tract and skin, and their subsequent initial encounter with cellular and humoral elements of the innate and adaptive immune response. An understanding of these host-spore interactions and the very early immune responses to the spores as they initiate the germination process will likely permit the development of an interventional vaccine or drug strategy that would act prior to the germination of spores and outgrowth of the vegetative form within the host and thus prevent development of Anthrax. We have identified mouse cell types involved in initial B. anthracis spore contact and will now analyze signaling pathways activated after spore entry and ingestion. We will define host cell receptors and spore-ligands involved in spore uptake and induction of intracellular activation pathways that affect intracellular spore survival. Multiple gene- targeted mice will be used to identify these pathways which promote or block spore killing bi phagocytic cells. We will test the effects of anti-spore antibodies on the fate of spores in vivo. These goals will be achieved by a combination of flow cytometric analysis and biochemical analysis using in vitro cells lines and primary phagocytes. If we can induce passive protective immunity with antibodies, we will attempt to elicit similar vaccine-induced immune responses and test the effects of these in long-term memory responses and determine the intracellular fate of spores if they are opsonized with antibodies to different spore targets. By identifying the spore-associated target molecules of these antibodies, we will be able to identify potential mechanisms to rapidly inactivate spores prior to establishment of infectious loci and vegetative cell outgrowth resulting in death from toxemia and septicemia. Therapeutic strategies of this nature would be a major supplement to the current PA-based vaccines as well as to the current recommended antibiotic regimens and in the case of multi-resistant B. anthracis strains engineered to produce additional toxins. Public Health Relevance: Bacillus anthracis spore dispersal as an agent of terrorism remains as an important issue to both civilian and military personnel. The exosporium, being the outermost layer of the spore stage of this organism, is the first point of contact of spores with host cells. By defining the molecules on the surface of spores and the receptors on host cells we may be able to develop interventional strategies to induce immune protection or drugs that will inactivate or destroy spores thus preventing bacterial development, the elaboration of toxins, and death.

描述（由申请人提供）：使用炭疽芽孢杆菌作为生物武器，取决于其在环境中的孢子分散，进入体内的孢子，人类宿主细胞的孢子吸收，宿主中孢子的发芽以及宿主对宿主植入植物细胞所赋予的毒品的反应的病理后果。对孢子进入宿主的机制知之甚少，包括气道中有针对性细胞类型的性质，消化道和皮肤，以及随后与先天和适应性免疫反应的细胞和幽默元素的初步相遇。对这些宿主孢子相互作用的理解以及对孢子的早期免疫反应在发芽过程中可能会允许开发介入疫苗或药物策略，该疫苗或药物策略在宿主内孢子和营养形式的发芽之前会起作用，从而制定植物中的生长，从而防止炭疽病的发展。我们已经鉴定出与初始芽孢杆菌孢子接触中涉及的小鼠细胞类型，现在将分析孢子进入和摄入后激活的信号通路。我们将定义涉及孢子摄取的宿主细胞受体和孢子 - 配体，并诱导影响细胞内孢子存活的细胞内激活途径。多个基因靶向小鼠将用于识别这些促进或阻断孢子杀死BI吞噬细胞的途径。我们将测试抗孢子抗体对体内孢子命运的影响。这些目标将通过使用体外细胞系和主要吞噬细胞的流式细胞仪分析和生化分析的结合来实现。如果我们能够用抗体诱导被动保护性免疫，我们将尝试引起类似的疫苗诱导的免疫反应并测试这些疫苗在长期记忆反应中的影响，并确定孢子的细胞内命运，如果它们用抗体对不同孢子靶标的抗体进行了调整。通过鉴定这些抗体的孢子相关靶标分子，我们将能够在建立感染性基因座和营养细胞出生生物之前鉴定出潜在的机制，从而快速失活孢子，从而导致毒血症和败血症死亡。这种性质的治疗策略将是当前基于PA的疫苗以及当前推荐的抗生素方案的主要补充，并且在多种耐药性炭疽杆菌菌株中，该抗生素菌株设计用于产生其他毒素。公共卫生相关性：作为恐怖主义的代理人，炭疽芽孢杆菌孢子散布仍然是平民和军事人员的重要问题。外孢子是该生物体的孢子阶段的最外层，是孢子与宿主细胞接触的第一点。通过定义孢子表面和宿主细胞上的受体的分子，我们可能能够开发介入免疫保护或会灭活或破坏孢子的药物的介入策略，从而防止细菌发育，对毒素的阐述和死亡。