NK cells in host defense against invasive aspergillosis

描述(申请人提供)：侵袭性肺曲霉菌病，一种常见的免疫抑制并发症，尽管目前有可用的治疗方法，但预后非常差。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反应中的作用，但其他效应细胞在宿主防御这种生物中的作用还不是很清楚。自然杀伤(NK)细胞是淋巴细胞的一个亚群，在对肿瘤细胞、移植的同种异体细胞和几种微生物的免疫反应中起重要作用。我们的初步研究表明，NK细胞对中性粒细胞减少的侵袭性曲霉病小鼠的宿主生存至关重要，在这种感染的背景下，它们向肺的募集可能是由CC趋化因子配体MCP-1/CCL2介导的。此外，自然杀伤细胞衍生的干扰素-伽马(干扰素-伽马)似乎可以增加肺部真菌的清除。因此，我们假设NK细胞是中性粒细胞减少的宿主抵抗侵袭性曲霉病的天然防御的组成部分，增强NK细胞向肺的募集或增强其效应器功能将改善侵袭性曲霉病的结局。我们将通过检测侵袭性肺曲霉病小鼠模型中的下列特定目标来解决这些假设：1)确定NK细胞在体外对曲霉菌的活性，并确定它们在侵袭性曲霉病中对宿主防御的贡献；2)检测趋化因子配体MCP-1/CCL2及其受体CCR2在侵袭性曲霉病中NK细胞向肺内募集的作用；以及3)评估NK细胞来源的干扰素-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为NK细胞在侵袭性曲霉病中作为肺部天然宿主防御介质的作用提供重要的新见解，并将导致这种毁灭性感染的新疗法的开发。

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.