NK cells in host defense against invasive aspergillosis

描述（由申请人提供）：侵袭性曲霉病是免疫功能低下患者常见的真菌感染，预后较差。在免疫功能低下的宿主中，对侵袭性曲霉病免疫反应的组成部分的全面了解是很重要的，因为它可能导致开发新的治疗方法，旨在提高宿主对这种感染的防御。在上一个资助期，我们建立了NK细胞在抵御中性粒细胞减少宿主感染方面的关键作用，并证明NK细胞是干扰素的主要来源。（IFN-?）。我们目前的初步研究表明NK细胞活化对宿主有益，NK细胞衍生的IFN-？介导趋化因子配体CXCL9、CXCL10和CXCL11的肺表达，并且表达这些配体受体CXCR3的效应白细胞在侵袭性曲霉病中运输到肺对侵袭性曲霉病的宿主防御至关重要。因此，我们假设NK细胞的激活和NK细胞诱导干扰素-3诱导的elr阴性CXC趋化因子对侵袭性曲霉病的宿主防御至关重要。我们拟在以下几个方面验证这些假设：1)探讨NK细胞活化在侵袭性曲霉病宿主防御中的作用机制；2)探讨NK细胞在侵袭性曲霉病中介导干扰素γ诱导的CXC趋化因子肺表达中的作用；3)确定干扰素γ诱导的CXC趋化因子在宿主防御侵袭性曲霉病中的作用。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，体内细胞耗竭和过继转移策略，以及体外免疫技术来实现这些目标。拟议的研究与公共卫生相关，因为它们应该在一种重要的人类疾病中定义以前未被认识到的宿主防御机制，并展望这些机制可以在治疗上被操纵以使患者受益。公共卫生相关性：侵袭性肺曲霉病是免疫力低下患者的常见感染，如癌症患者或器官移植患者。尽管接受了最好的治疗，许多感染这种病毒的病人还是死于这种疾病。我们想要了解免疫系统中帮助抵抗这种感染的成分。目标是利用这些信息来开发新的治疗方法，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.