NK cells in host defense against invasive aspergillosis

侵袭性曲霉病是免疫功能低下患者常见的真菌感染 预后很差。对免疫应答成分的透彻了解 侵袭性曲霉病在免疫受损宿主的背景下是重要的，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抵抗力。在……里面 在上一个资助期，我们建立了NK细胞，使其对抵御感染至关重要 中性粒细胞减少的宿主，早期证实NK细胞是干扰素的主要来源 感染。我们对当前提议的初步研究表明，NK细胞的激活是有益的 对于宿主来说，NK细胞来源的干扰素-β介导了趋化因子配体CXCL9的肺表达， CXCL10和CXCL11，以及表达这些受体CXCR3的效应白细胞 侵袭性曲霉病中的配体、进入肺的交通对侵袭性曲霉病的宿主防御是必不可少的。 曲霉病。因此，我们假设NK细胞的激活和NK细胞的诱导 干扰素诱导的ELR阴性CXC趋化因子在侵袭性宿主防御中起关键作用 曲霉病。我们建议在以下具体目标下检验这些假设：1)检验 侵袭性曲霉病中NK细胞活化在宿主防御中的作用机制 NK细胞在介导干扰素-γ诱导的CXC趋化因子肺表达中的作用 侵袭性曲霉病；以及3)确定干扰素-γ诱导的CXC趋化因子在 侵袭性曲霉病的宿主防御。我们建议使用转基因和基因敲除动物 在侵袭性曲霉病小鼠模型中，体内细胞耗尽和采用转移策略，以及 体外免疫学技术来实现这些目标。建议的研究与公众有关 健康，因为他们应该定义以前未识别的宿主防御机制 人类疾病，这些机制有可能被操纵来治疗 让患者受益。

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-¿-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.