NK cells in host defense against invasive aspergillosis

描述(申请人提供)：侵袭性曲霉病是一种常见的真菌感染的免疫功能低下的患者，具有较差的预后。在免疫受损的宿主的背景下，彻底了解侵袭性曲霉病的免疫反应的组成部分是重要的，因为这可能导致旨在改善宿主对这种感染的防御的新治疗方法的开发。在上一个资助阶段，我们建立了NK细胞对抵御中性粒细胞减少宿主感染的关键作用，并证明NK细胞是干扰素的主要来源。(干扰素-？)在感染的早期。我们对本方案的初步研究表明，NK细胞活化对宿主有利，NK细胞来源的干扰素？介导肺内趋化因子配体CXCL9、CXCL10和CXCL11的表达，以及表达这些配体的受体CXCR3的效应白细胞在侵袭性曲霉病中向肺的运输是侵袭性曲霉病宿主防御所必需的。因此，我们假设NK细胞的激活和NK细胞对干扰素-3诱导的ELR阴性的CXC趋化因子的诱导对侵袭性曲霉病的宿主防御至关重要。我们建议在以下特定目标下验证这些假设：1)研究侵袭性曲霉病中NK细胞激活在宿主防御中的机制；2)研究NK细胞在侵袭性曲霉病中介导干扰素-γ诱导的CXC趋化因子在肺表达中的作用；以及3)确定干扰素-γ诱导的CXC趋化因子在侵袭性曲霉病宿主防御中的作用。我们建议在侵袭性曲霉病小鼠模型中使用转基因和基因敲除动物，体内细胞耗尽和过继转移策略，以及体外免疫学技术来实现这些目标。这项拟议的研究与公共卫生相关，因为它们应该定义一种重要的人类疾病中以前未被识别的宿主防御机制，并有望通过治疗来操纵这些机制，使患者受益。公共卫生相关性：侵袭性肺曲霉菌病是免疫力低下患者的常见感染，如癌症或器官移植患者。尽管接受了最好的治疗，但许多感染这种感染的患者还是死于这种感染。我们想了解帮助抵抗这种感染的免疫系统的组成部分。目标是利用这些信息开发新的治疗方法，以加强对这种感染的免疫反应。

DESCRIPTION (provided by applicant): Invasive aspergillosis is a common fungal infection in immunocompromised patients and carries a poor prognosis. A thorough understanding of the components of the immune response to invasive aspergillosis in the context of an immunocompromised host is important, because it may lead to the development of new treatments aimed at improving the host defense against this infection. In the last funding period, we established NK cells to be critical to defense against the infection in the neutropenic host and demonstrated NK cells to be the major source of interferon-? (IFN-?) early in the infection. Our preliminary studies for the current proposal indicate that NK cell activation is beneficial to the host, that NK cell-derived IFN-? mediates the lung expression of the chemokine ligands CXCL9, CXCL10, and CXCL11, and that effector leukocytes expressing CXCR3, the receptor for these ligands, traffic to the lung in invasive aspergillosis are essential for host defense in invasive aspergillosis. We therefore hypothesize that activation of NK cells and NK cell induction of the interferon-3-inducible ELR-negative CXC chemokines are critical to host defense in invasive aspergillosis. We propose to test these hypotheses under the following specific aims: 1) To examine the mechanism of NK cell activation in host defense in invasive aspergillosis; 2) To investigate the role of NK cells in mediating the lung expression of interferon gamma-inducible CXC chemokines in invasive aspergillosis; and 3) To determine the role of interferon gamma-inducible CXC chemokines in host defense against invasive aspergillosis. We propose to use transgenic and gene knockout animals in a mouse model of invasive aspergillosis, in vivo cell depletion and adoptive transfer strategies, and in vitro immunologic techniques to achieve these goals. The proposed studies are relevant to public health in that they should define previously unrecognized host defense mechanisms in an important human illness, with the prospect that these mechanisms could be manipulated therapeutically to benefit patients. PUBLIC HEALTH RELEVANCE: Invasive pulmonary aspergillosis is a common infection in patients with weakened immunity, such as patients with cancer or organ transplantation. Many of the patients who catch this infection die of it despite receiving the best available treatment. We want to understand the components of the immune system that help fight off this infection. The goal is to use this information to develop new treatments to strengthen the immune response to this infection.