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

描述（由申请人提供）：本项目的具体目的是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，宿主免疫反应以及铁在真菌与宿主相互作用中的作用。IA是一种在全球范围内日益重要的未充分研究的疾病，仅在美国每年就导致超过3，500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，IA的重要性正在增加，这些技术正在扩大对A易感的患者范围。烟曲霉感染例如，虽然移植患者仍然是风险最大的患者群体，但免疫抑制疗法现在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。随着免疫功能低下患者数量的增加，A.烟曲霉和其他侵入性霉菌的数量无疑将继续增加。为了确定新的和有前途的治疗靶点来治疗这种无处不在的真菌感染，研究人员采用了系统生物学方法来了解真菌的毒力途径。这里提出的项目将这种方法应用于宿主反应，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方面的，但宿主和A。fumigatus是操纵巨噬细胞和上皮细胞中的铁水平。铁稳态由蛋白质控制系统调节，这些蛋白质通过几个相互交织的反馈回路连接。这使得理解介导细胞因子产生对铁水平的影响的机制变得复杂。拟议项目的重点是阐明免疫蛋白和参与肺泡巨噬细胞和肺上皮细胞铁稳态的关键蛋白的网络，目的是确定曲霉菌感染期间铁调节的关键驱动因素。该项目的核心发现工具将是构建网络的动态数学模型，该模型对关键蛋白质扰动下的动态响应和反馈回路的影响进行编码。 公共卫生相关性：本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，宿主免疫反应以及铁在真菌与宿主相互作用中的作用。它影响了我们为这种未充分研究的疾病确定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.