Immune regulation to Coccidioides infection

项目摘要 球孢子菌病，或山谷热，是由于吸入真菌球孢子菌。对健康的影响 山谷热感染的差异很大，对影响山谷热感染的生物因素知之甚少。 感染后症状和健康并发症的严重程度。谷热诊断， 由于缺乏对宿主的基本免疫知识， 对Coccidioides的回应我们小组公布的数据表明， 球孢子菌感染可能是调节性T细胞频率和功能能力升高的结果， 调节性T细胞频率可以预测患者诊断时的疾病结果。该提案旨在界定 调节性T细胞在控制球孢子菌感染应答中的机制作用及 抑制性受体在免疫真菌控制中的作用。这项研究的总体目标是提供基本的 有关谷热免疫反应的知识，填补知识空白，作为改进的基础 诊断，治疗和疫苗开发的快速扩展的真菌疾病。为了实现这一目标，我们 将定义T细胞的调节机制，感染过程中的动力学和定位，并操纵 在小鼠感染模型中使用免疫调节抗体的调节和效应T细胞。虽然 尽管目前尚不清楚具体细节，但细胞免疫应答早已被证明对有效免疫至关重要。 球孢子菌感染在一些患者中，山谷热导致严重或长期的临床疾病， 严重的健康影响，包括慢性肺结节和肺外扩散。这 该提案将评估球孢子菌感染期间免疫调节如何调节真菌清除。

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.