NK cells in host defense against invasive aspergillosis

描述（由申请人提供）：侵袭性肺曲霉菌病是免疫抑制的常见并发症，尽管目前有治疗方法，但预后极差。 虽然大量的工作已经评估了中性粒细胞在肺对这种病原体的先天免疫应答中的作用，但其他效应细胞在宿主防御这种生物体中的作用尚不清楚。 自然杀伤（NK）细胞是在针对肿瘤细胞、移植的同种异体细胞和几类微生物的免疫应答中重要的淋巴细胞的子集。 我们的初步研究表明，NK细胞是至关重要的宿主生存在侵袭性曲霉菌感染的小鼠，并在这种感染的设置，其招聘到肺可能是由CC趋化因子配体，MCP-1/CCL 2介导的。 此外，NK细胞衍生的干扰素-γ（IFN-γ）似乎增加真菌从肺中的清除。 因此，我们假设NK细胞是先天性宿主防御侵袭性曲霉病的组成部分，并增强NK细胞的招募到肺或增强其效应功能，将改善侵袭性曲霉病的结果。 我们将通过在侵袭性肺曲霉菌病小鼠模型中检查以下具体目的来解决这些假设：1）确定NK细胞对曲霉菌的体外活性，并确定它们在侵袭性曲霉菌病中对宿主防御的体内贡献; 2）检测趋化因子配体MCP-1/CCL 2及其受体CCR 2在侵袭性曲霉病中NK细胞向肺募集中的作用; 3）研究NK细胞源性IFN-γ在体内外介导抗真菌宿主防御中的作用。 我们希望，拟议的研究将提供重要的新见解NK细胞作为介质的先天性宿主防御在肺部侵袭性曲霉菌病的作用，他们也将导致开发新的疗法，这种毁灭性的感染。

DESCRIPTION (provided by applicant): Invasive pulmonary aspergillosis, a common complication of immunosuppression, carries a strikingly poor outcome despite currently available therapy. While substantial work has evaluated the role of neutrophils in the lung's innate immune response to this pathogen, the role of other effector cells in host defense against this organism is less clear. Natural killer (NK) cells are a subset of lymphocytes important in immune responses against tumor cells, transplanted allogeneic cells, and several classes of micro-organisms. Our preliminary studies indicate that NK cells are critical to host survival in neutropenic mice with invasive aspergillosis and that their recruitment to the lung in the setting of this infection may be mediated by the CC chemokine ligand, MCP-1/CCL2. Moreover, NK cell-derived interferon-gamma (IFN-gamma) appears to augment fungal clearance from the lung. We therefore hypothesize that NK cells are integral components of innate host defense against invasive aspergillosis in neutropenic hosts, and that enhancing the recruitment of NK cells to the lung or augmenting their effector functions will improve the outcome of invasive aspergillosis. We shall address these hypotheses by examining the following Specific Aims in a murine model of invasive pulmonary aspergillosis: 1) To determine the in vitro activity of NK cells against Aspergillus and to determine their in vivo contribution to host defense in invasive aspergillosis; 2) To examine the role of the chemokine ligand, MCP-1/CCL2, and its receptor, CCR2, in the recruitment of NK cells to the lungs in invasive aspergillosis; and 3) To evaluate the role of NK cell-derived IFN-gamma in mediating anti-fungal host defense in vitro and in vivo. We hope that the proposed studies will provide important new insights into the role of NK cells as mediators of innate host defense in the lung in invasive aspergillosis, and that they will also result in development of novel therapies for this devastating infection.