The Role of Rac and ROS in the Control of Aspergillus Infection

描述（由申请方提供）：烟曲霉是一种重要的机会致病菌，人类每天通过吸入孢子进入肺部而暴露于该菌。在健康个体中，先天免疫系统足以防止这些孢子的生长、传播和萌发。然而，在免疫功能低下的患者中，例如那些接受免疫抑制治疗，遗传性免疫缺陷或感染HIV/AIDS的患者，侵袭性曲霉病可能发展并危及生命。先天免疫网络的完整补充和杀死健康个体孢子的机制仍然知之甚少。这项研究的总体目标是更好地了解先天免疫细胞如何控制健康个体的曲霉菌感染，以及疾病如何在免疫功能低下的个体中不受控制地进行。斑马鱼胚胎宿主模型系统非常适合回答这些问题。斑马鱼胚胎尚未发育出适应性免疫系统，这使我们能够专门研究先天免疫反应。此外，胚胎是半透明的，允许细胞迁移、吞噬作用和孢子活力和萌发的实时成像。在与真菌发病机理实验室的合作中，我们最近开发了一种斑马鱼曲霉感染模型，该模型概括了人类疾病的许多方面。我们建议利用这个模型来研究特定的免疫机制的要求，如生产活性氧（ROS），在控制曲霉。已知ROS对控制曲霉菌很重要，但它们究竟如何起作用以及它们是否对细胞间信号传导、趋化性或杀真菌活性最重要尚不清楚。这项研究是由以下假设驱动的：ROS在不同的先天免疫细胞类型中响应曲霉菌感染时发挥多种互补作用。这项提议的优势在于斑马鱼实验室和真菌致病实验室之间的合作，使我们能够探测宿主-病原体相互作用的双方。

DESCRIPTION (provided by applicant): Aspergillus fumigatus is an important opportunistic pathogen to which humans are exposed every day via inhalation of spores into the lungs. In healthy individuals, the innate immune system is sufficient to prevent the growth, dissemination, and germination of these spores. However in immunocompromised patients, such as those undergoing immunosuppressive therapies, with genetic immunodeficiencies, or infected with HIV/AIDs, invasive aspergillosis can develop and is life-threatening. The full complement of innate immune networks and mechanisms that kill spores in healthy individuals remain poorly understood. The overarching goal of the proposed research is to better understand how innate immune cells control Aspergillus infections in healthy individuals and how disease is able to proceed uncontrolled in immunocompromised individuals. The zebrafish embryo host model system is ideally suited to answer these questions. Zebrafish embryos have not yet developed an adaptive immune system, allowing us to specifically study innate immune responses. Additionally, the embryos are translucent, allowing for live imaging of cell migration, phagocytosis, and spore viability and germination. In collaboration with a fungal pathogenesis lab we have recently developed an Aspergillus infection model in zebrafish which recapitulates many aspects of the human disease. We propose to utilize this model to study the requirement for specific immune mechanisms, such as production of reactive oxygen species (ROS), in the control of Aspergillus. ROS are known to be important to control Aspergillus, but exactly how they act and whether they are most important for cell-cell signaling, chemotaxis, or fungicidal activity is unknown. This research is driven by the hypothesis that ROS play multiple complementary roles in different innate immune cell types in response to Aspergillus infection. The strength in this proposal lies in the collaboration between a zebrafish lab and a fungal pathogenesis lab, allowing us to probe both sides of the host-pathogen interaction.