The systems biology of iron homeostasis and the immune response to Aspergillus

描述(申请人提供)：这个项目的具体目的是为了更好地了解烟曲霉的生物学和毒力，侵袭性曲霉病(IA)的病原体，宿主的免疫反应，以及铁在真菌和宿主之间相互作用中的作用。IA是一种在全球范围内日益重要的未被研究的疾病，仅在美国每年就导致3500多人死亡。由于同种异体和自体干细胞移植数量的大幅增加，以及医疗技术的进步，扩大了易受烟曲霉菌感染的患者的范围，IA的重要性正在增长。例如，虽然移植患者仍然是风险最高的患者群体，但免疫抑制疗法现在被常规用于治疗更常见的疾病，包括哮喘、类风湿性关节炎和胃肠道疾病。随着免疫缺陷患者数量的增加，由烟曲霉等侵袭性霉菌引起的侵袭性感染的重要性无疑将继续增加。为了确定治疗这种无处不在的真菌感染的新的和有希望的治疗靶点，研究人员采用了一种系统生物学的方法来了解导致毒力的真菌途径。这里提出的项目将这种方法应用于宿主的反应，朝着整合宿主和真菌途径的最终目标迈出了一步。虽然宿主的反应是多管齐下的，但宿主和烟曲霉菌之间相互作用的一个中心因素是对巨噬细胞和上皮细胞中铁水平的控制。铁稳态是由蛋白质控制系统调节的，这些蛋白质通过几个相互交织的反馈环连接在一起。这使人们对细胞因子产生对铁水平影响的机制的理解变得复杂起来。该项目的重点是阐明参与肺泡巨噬细胞和肺上皮细胞铁稳态的免疫蛋白和关键蛋白的网络，目的是确定曲霉感染过程中铁调节的关键驱动因素。该项目的核心发现工具将是要构建的网络的动态数学模型，该模型编码关键蛋白质扰动下的动态响应和反馈环的影响。 公共卫生相关性：该项目旨在更好地了解侵袭性曲霉病(IA)的病原体烟曲霉的生物学和毒力，宿主的免疫反应，以及铁在真菌和宿主之间相互作用中的作用。它影响了我们为这种未被研究的疾病寻找新的治疗方法的能力。

DESCRIPTION (provided by applicant): The specific aims of this project are designed to better understand the biology and virulence of Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA), the host immune response, and the role of iron in the interaction between fungus and host. IA is an understudied disease of growing significance worldwide that causes over 3,500 annual deaths in the U.S. alone. The significance of IA is growing due to substantial increases in the number of allogenic and autologous stem cell transplants, as well as advances in medical technologies that are expanding the spectrum of patients susceptible to A. fumigatus infections. For example, while transplant patients remain the patient population most at risk, immunosuppression therapies are now routinely used to treat more common diseases including, asthma, rheumatoid arthritis, and gastrointestinal disorders. With the rising number of immunocompromised patients, the significance of invasive infections caused by A. fumigatus and other invasive moulds will undoubtedly continue to increase. In order to identify new and promising therapeutic targets to treat infection with this ubiquitous fungus, researchers have incorporated a systems biology approach to understand the fungal pathways contributing to virulence. The project proposed here applies this approach to the host response, a step toward the ultimate goal of integrating host and fungal pathways. While the host response is multi-pronged, a central factor in the interplay between the host and A. fumigatus is the manipulation of iron levels in both macrophages and epithelial cells. Iron homeostasis is regulated by a control system of proteins that are connected through several intertwined feedback loops. This complicates an understanding of the mechanisms that mediate the effect of cytokine production on iron levels. The focus of the proposed project is to elucidate the network of immune proteins and key proteins involved in iron homeostasis in both alveolar macrophages and lung epithelial cells, with the goal of identifying key drivers of iron regulation during Aspergillus infection. Th central discovery tool in the project will be a dynamic mathematical model of the network to be constructed that encodes the dynamic response and the effect of feedback loops under perturbations of key proteins. PUBLIC HEALTH RELEVANCE: This project is designed to better understand the biology and virulence of Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA), the host immune response, and the role of iron in the interaction between fungus and host. It impacts our ability to identify novel therapeutic treatments for this understudied disease.