Cytotoxic Cell Dysfunction in HGA

描述(由申请人提供)：本提案旨在剖析吞噬细胞性假丝酵母菌感染引起轻度和严重疾病的免疫致病机制。我们先前确定了支持性数据，并提供了初步研究，表明NK和NKT细胞在炎症性疾病诱导中的重要性。此外，在小鼠和人类身上的研究都提供了巨噬细胞激活和吞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化解炎症能力的缺陷细胞毒性细胞反应有关，因此我们建议研究吞噬细胞性弧菌感染是否导致NK、NKT和CD8T淋巴细胞等细胞毒性细胞直接杀伤细胞的缺陷，但不改变诱导的促炎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进行体外分析来研究这一点，作为一种高度定义和控制的实验方法，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够阐明吞噬细胞性弧菌感染所引起的特定免疫异常，并使我们能够更集中和更深入地寻找靶标，从而为减少感染的严重后果的治疗干预提供新的机会。 与公共卫生相关：人类粒细胞无形体病是一种新出现的、由壁虱传播的感染，可以是轻微的或致命的。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的激活而导致的，而免疫系统随后没有被适当地关闭。这项应用建议详细检查是否可以在实验室和小鼠的活体感染模型中识别缺陷。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的宿主细胞功能的新信息。

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.