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

描述(申请人提供)：烟曲霉是一种重要的机会性病原体，人类每天通过吸入孢子进入肺部而暴露于这种病原体。在健康的个体中，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，如接受免疫抑制治疗的患者、有遗传免疫缺陷的患者或感染艾滋病毒/艾滋病的患者，侵袭性曲霉病可能会发展，并危及生命。完整的先天免疫网络和杀死健康个体孢子的机制仍然知之甚少。这项拟议研究的首要目标是更好地了解先天性免疫细胞如何控制健康个体的曲霉感染，以及疾病如何能够在免疫受损的个体中不受控制地发展。斑马鱼胚胎宿主模型系统非常适合回答这些问题。斑马鱼胚胎还没有开发出适应性免疫系统，这让我们能够专门研究先天免疫反应。此外，胚胎是半透明的，允许对细胞迁移、吞噬作用以及孢子存活和萌发进行实时成像。在与真菌发病实验室的合作中，我们最近开发了一种斑马鱼曲霉菌感染模型，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在曲霉控制中对特定免疫机制的需求，例如产生活性氧物种(ROS)。众所周知，ROS对控制曲霉很重要，但它们到底是如何发挥作用的，以及它们对细胞信号、趋化性或杀菌活性是否最重要，目前尚不清楚。这项研究是由一种假设驱动的，即ROS在不同类型的先天性免疫细胞对曲霉感染的反应中发挥着多种互补作用。这项建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，使我们能够探索宿主和病原体相互作用的两个方面。

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.