Cytotoxic Cell Dysfunction in HGA

HGA 中的细胞毒性细胞功能障碍

• 批准号: 8177048
• 负责人: JOHN STEPHEN Dumler
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177048
• 关键词: Admission activity; Adrenal Cortex Hormones; Anaplasma phagocytophilum; Animals; Antigen-Presenting Cells; Antigens; Bacteremia; Bacteria; Bovine Anaplasmosis; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical; Cytolysis; Data; Defect; Dendritic Cells; Disease; Disease model; Dissociation; Equus caballus; Event; Functional disorder; Granzyme; Hemophagocytic Syndrome; Histopathology; Human; Immune; Immune system; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-12; Laboratories; Lead; Lesion; Life; Light; Link; Macrophage Activation; Metalloproteases; Modeling; Mus; Natural Immunity; Natural Killer Cells; Organism; Pathogenesis; Process; Production; Reactive Nitrogen Species; Research; SCID Mice; Septic Shock; Serum; Severities; Signal Pathway; Systemic disease; T-Lymphocyte; Therapeutic Intervention; Tick-Borne Infections; Ticks; Tissues; Toxic Shock Syndrome; adaptive immunity; base; cell killing; combat; cytokine; cytotoxic; cytotoxicity; in vivo; killings; macrophage; mouse model; pathogen; perforin; reactive oxygen intermediate; response; vector

DESCRIPTION (provided by applicant): This proposal is directed at dissecting the immunopathogenetic mechanisms of A. phagocytophilum infection in its dichotomous ability to cause mild and severe disease. We previously identified supportive data and provide preliminary studies that show the importance of NK and NKT cells in the induction of inflammatory disease. Moreover, studies in mice and humans both provide evidence of macrophage activation and hemophagocytic syndrome-like processes as the potential basis of inflammatory tissue injury and severe disease. Since macrophage activation and hemophagocytic syndromes are biologically linked to defective cytotoxic cell responses that lack the ability to dampen and resolve inflammation, we propose here to study whether A. phagocytophilum infection induces defects in direct cell killing by cytotoxic cells such as NK, NKT, and CD8 T lymphocytes, yet does not alter the profile of induced proinflammatory and macrophage activating cytokines. We expect to study this by in vitro analyses using purified cells and bacteria as a highly defined and controlled experimental approach and to verify the results in vivo using the mouse model we developed. We anticipate that these studies could shed light on the specific immunological abnormalities that occur with A. phagocytophilum infection and allow a more focused and intensive search for targets that could provide new opportunities for therapeutic interventions that diminish the severe consequences of infection. PUBLIC HEALTH RELEVANCE: Human granulocytic anaplasmosis is an emerging tick-borne infection that can be mild or fatal. Research indicates that the bacterium can induce a disease that results from activation of the immune system that then is not properly turned off. This application proposes to examine in detail whether the defect can be identified in the laboratory and in a live infection model of the disease in mice. This could lead to new information on how disease occurs with this organism and others, and perhaps new information about ways to combat this infection or to change host cell function in other diseases.

描述（由申请人提供）：本提案旨在剖析A.嗜吞噬细胞菌感染在其引起轻度和重度疾病的二分能力。我们以前确定了支持性数据，并提供了初步研究，表明NK和NKT细胞在诱导炎症性疾病中的重要性。此外，在小鼠和人类中的研究都提供了巨噬细胞活化和噬血细胞综合征样过程作为炎性组织损伤和严重疾病的潜在基础的证据。由于巨噬细胞活化和噬血细胞综合征在生物学上与缺乏抑制和解决炎症能力的缺陷性细胞毒性细胞反应有关，我们在这里提出研究A。嗜吞噬细胞感染会诱导NK、NKT和CD 8 T淋巴细胞等细胞毒性细胞直接杀伤细胞的缺陷，但不会改变诱导的促炎细胞因子和巨噬细胞活化细胞因子的特征。我们希望通过使用纯化的细胞和细菌作为高度定义和控制的实验方法进行体外分析来研究这一点，并使用我们开发的小鼠模型在体内验证结果。我们期望这些研究能阐明A.本发明的目的是提供一种新的方法来抑制嗜吞噬细胞菌感染，并允许更集中和深入地寻找可以为减少感染的严重后果的治疗干预提供新机会的靶标。 公共卫生相关性：人粒细胞无形体病是一种新出现的蜱传感染，可能是轻度或致命的。研究表明，这种细菌可以诱发一种疾病，这种疾病是由于免疫系统激活而导致的，而免疫系统没有被正确关闭。本申请提出详细检查是否可以在实验室中和在小鼠中的疾病的活感染模型中鉴定缺陷。这可能会带来关于这种生物体和其他生物体如何发生疾病的新信息，也许还会带来关于如何对抗这种感染或改变其他疾病中宿主细胞功能的新信息。