Immune regulation to Coccidioides infection - PROJECT SUMMARY Coccidioidomycosis, or Valley fever, is caused by inhalation of the fungus Coccidioides. The health impacts of Valley fever infection vary dramatically, and little is known about the biological factors that influence the severity of symptoms and health complications experienced following infection. Valley fever diagnosis, treatment and vaccine development have been hampered by a lack of basic immune knowledge about the host response to Coccidioides. Published data from our group determined that the inability of patients to resolve Coccidioides infection may be a result of elevated regulatory T cell frequency and functional capacity, and that regulatory T cell frequency may predict patient disease outcome at diagnosis. This proposal seeks to define the mechanistic role of regulatory T cells in controlling responses to Coccidioides infection and the influence of inhibitory receptors in immune fungal control. The overall goal of this research study is to provide fundamental knowledge about immune responses to Valley fever, filling gaps in knowledge, as a foundation to improve diagnosis, treatment and vaccine development for a rapidly expanding fungal disease. To achieve this goal, we will define the mechanisms of T cell regulation, kinetics and localization during infection, and manipulate regulatory and effector T cells using immune modulating antibodies in mouse infection models. Although the details are still unclear, cellular immune responses have long been shown to be critical for effective immunity to Coccidioides infection. In some patients, Valley fever results in a severe or prolonged clinical illness with dramatic health impacts, including chronic pulmonary nodules and dissemination outside the lungs. This proposal will evaluate how immune regulation modulates fungal clearance during Coccidioides infection.
