Cytotoxic Cell Dysfunction in HGA

HGA 中的细胞毒性细胞功能障碍

基本信息

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
项目类别：
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

项目摘要

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）：本提案旨在剖析嗜吞噬细胞放线菌感染的免疫致病机制，了解其引起轻度和重度疾病的二分能力。我们之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，对小鼠和人类的研究都提供了巨噬细胞激活和噬血细胞综合征样过程作为炎症组织损伤和严重疾病的潜在基础的证据。由于巨噬细胞激活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细胞毒性细胞反应缺陷有关，因此我们在此建议研究嗜吞噬细胞放线菌感染是否会诱导细胞毒性细胞（例如 NK、NKT 和 NK）直接杀伤细胞的缺陷。 CD8 T 淋巴细胞，但不会改变诱导的促炎细胞因子和巨噬细胞激活细胞因子的特征。我们希望通过使用纯化的细胞和细菌作为高度定义和受控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来验证体内结果。我们预计这些研究可以揭示嗜吞噬细胞球菌感染时发生的特定免疫异常，并可以更加集中和深入地寻找目标，从而为减少感染严重后果的治疗干预提供新的机会。公共卫生相关性：人类粒细胞无形体病是一种新出现的蜱传感染，可能是轻微的，也可能是致命的。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后未正确关闭而引起的。该申请旨在详细检查是否可以在实验室和小鼠疾病的活体感染模型中识别出该缺陷。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，或许还可能带来关于对抗这种感染或改变其他疾病中宿主细胞功能的方法的新信息。