Neutrophils and adaptive immunity 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，预后不良。深入了解免疫功能低下宿主对侵袭性曲霉病免疫反应的组成部分是很重要的，因为它可能导致开发旨在改善宿主对这种感染的防御的新治疗方法。以前的文献已经证明，正常的主机能够产生强大的和保护性的适应性免疫反应，对曲霉菌，但侵袭性曲霉病经常复发的曲霉菌病的主机，这表明这些主机无法产生保护性免疫的生物体在初始感染。在这种情况下，我们先前已经确定，肺内曲霉菌攻击后，血小板减少宿主在CD 11b+树突状细胞成熟和运输方面存在缺陷。在这个建议的初步数据，我们报告说，在初始挑战曲霉菌导致中性粒细胞减少症未能产生保护性免疫力，对随后的感染，并在NADPH氧化酶复合物的gp 91 phox组件缺陷的小鼠开发一个类似的树突状细胞表型的血小板减少症动物。因此，我们假设中性粒细胞是必要的保护性适应性免疫对侵袭性曲霉病的产生。我们建议在以下具体目标下检验这一假设：1）确定中性粒细胞对侵袭性曲霉病保护性适应性免疫发展的贡献; 2）确定中性粒细胞氧化爆发在侵袭性曲霉病中的作用。 树突状细胞介导的对曲霉菌的保护性适应性免疫的产生。我们建议使用新的和建立的动物模型和体内细胞耗竭和过继转移策略来实现这些目标。拟议的研究与公共卫生相关，因为它们应该在重要的人类疾病中定义一种新的宿主防御机制，前景是可以在治疗上操纵这种机制以使患者受益。

 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 immunocompromised hosts is important, because it may lead to the development of new treatments aimed at improving the host defense against this infection. Prior literature has documented that normal hosts are capable of generating a robust and protective adaptive immune response against Aspergillus, yet invasive aspergillosis often recurs in neutropenic hosts, suggesting that these hosts fail to generate protective immunity against the organism during the initial infection. In this context, we have previously established that neutropenic host have a defect in CD11b+ dendritic cell maturation and traffic after intrapulmonary challenge with Aspergillus. In the preliminary data for this proposal, we report that neutropenia during an initia challenge with Aspergillus results in failure to generate protective immunity against a subsequent infection and that mice deficient in the gp91phox component of NADPH oxidase complex develop a similar dendritic cell phenotype to neutropenic animals. We therefore hypothesize that neutrophils are necessary for the generation of protective adaptive immunity against invasive aspergillosis. We propose to test this hypothesis under the following specific aims: 1) To identify the contribution of neutrophils to the development of protective adaptive immunity against invasive aspergillosis; and 2) To define the role of neutrophil oxidative burst in generation of dendritic cell-mediated protective adaptive immunity to Aspergillus. We propose to use both novel and established animal models and in vivo cell depletion and adoptive transfer strategies to achieve these goals. The proposed studies are relevant to public health in that they should de- fine a novel host defense mechanism in an important human illness, with the prospect that this mechanism could be manipulated therapeutically to benefit patients.