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

• 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
• 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

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（由申请方提供）：炭疽芽孢杆菌作为生物武器的使用取决于其孢子在环境中的传播、进入人体、孢子被人体宿主细胞摄取、孢子在宿主中的萌发以及宿主对宿主内营养细胞产生的毒素的反应的病理后果。孢子进入宿主的机制知之甚少，包括气道、消化道和皮肤中靶细胞类型的性质，以及它们随后与先天性和适应性免疫反应的细胞和体液成分的最初相遇。了解这些宿主-孢子相互作用和孢子启动萌发过程时对孢子的非常早期的免疫反应，将可能允许开发干预性疫苗或药物策略，其将在孢子萌发和宿主内营养体生长之前起作用，从而防止炭疽的发展。我们已经确定了参与初始B的小鼠细胞类型。炭疽孢子接触，现在将分析孢子进入和摄入后激活的信号通路。我们将定义宿主细胞受体和孢子配体参与孢子摄取和诱导细胞内激活途径，影响细胞内孢子存活。将使用多基因靶向小鼠来鉴定促进或阻断孢子杀死双吞噬细胞的这些途径。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原代吞噬细胞的流式细胞术分析和生化分析的组合来实现。如果我们可以用抗体诱导被动保护性免疫，我们将尝试引发类似的疫苗诱导的免疫应答，并测试这些在长期记忆应答中的作用，并确定孢子的细胞内命运，如果它们用针对不同孢子靶标的抗体调理。通过鉴定这些抗体的孢子相关靶分子，我们将能够鉴定在建立感染位点和营养细胞生长导致毒血症和败血症死亡之前快速消灭孢子的潜在机制。这种性质的治疗策略将是目前基于PA的疫苗以及目前推荐的抗生素方案和多重耐药B的主要补充。炭疽菌菌株被改造以产生额外的毒素。公共卫生相关性：炭疽杆菌孢子传播作为一种恐怖主义制剂，对文职人员和军事人员来说仍然是一个重要问题。外孢壁是该生物体孢子阶段的最外层，是孢子与宿主细胞的第一个接触点。通过确定孢子表面的分子和宿主细胞上的受体，我们可能能够开发干预策略来诱导免疫保护或药物，这些免疫保护或药物将抑制或破坏孢子，从而防止细菌发育，毒素的产生和死亡。