Immune regulation to Coccidioides infection

项目总结 球孢子菌病，或谷热，是由吸入球孢子菌引起的。对健康的影响 谷热感染的比例差异很大，对影响山谷热感染的生物学因素知之甚少。 感染后症状的严重性和健康并发症。山谷热的诊断， 由于缺乏关于宿主的基本免疫知识，治疗和疫苗开发一直受到阻碍 对球虫类药物的反应。我们小组公布的数据表明，患者无法解决 球虫感染可能是调节性T细胞频率和功能能力增加的结果，并且 调节性T细胞频率可能在诊断时预测患者的疾病结果。这项提案旨在定义 调节性T细胞在控制球虫感染应答中的作用及其影响 免疫真菌控制中的抑制性受体。本研究性研究的总体目标是提供基本的 关于谷热免疫反应的知识，填补知识空白，作为改进的基础 一种迅速扩大的真菌疾病的诊断、治疗和疫苗开发。为了实现这一目标，我们 将确定T细胞在感染过程中的调节、动力学和定位的机制，并操纵 在小鼠感染模型中使用免疫调节抗体的调节性和效应性T细胞。尽管 细节仍不清楚，细胞免疫反应长期以来一直被证明是有效免疫的关键 对球虫的感染。在一些患者中，谷热会导致严重或延长的临床疾病 严重影响健康，包括慢性肺结节和向肺外扩散。这 该提案将评估免疫调节如何调节球虫感染期间的真菌清除。

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.