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

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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.