Regulatory T cell function in predicting Valley fever outcomes

项目摘要 球孢子菌病，被称为山谷热，是由真菌病原体（球孢子菌属）引起的地方性疾病。 加州的圣华金河谷、亚利桑那州、墨西哥北方和南美洲的干旱地区。发生率 加州呈上升趋势，有证据表明，在非流行地区也能发现这种疾病 包括华盛顿州。人口膨胀、旅行、探测和/或天气变化似乎是 导致了地方病流行区的扩大山谷热感染对健康的影响范围从 从表面到致命对于60%的人谁是感染，但不显示症状的山谷热， 这种疾病的影响可能很小。对于40%有症状的患者，大多数会显示症状 类似于流感，这种情况不需要治疗就可以解决。然而，这些患者可能会经历 长期严重损害健康。对于1%的患者，山谷热导致严重的 或长期的临床疾病，对健康造成严重影响，包括慢性肺结节或空洞， 误诊甚至死亡的可能性疾病经常被误诊为细菌感染， 导致在正确诊断之前进行了几轮抗生素治疗。山谷对健康的影响 因此，发热感染的差异很大，而对影响严重程度的生物因素知之甚少。 感染后的症状和健康并发症。 虽然细节尚不清楚，但细胞免疫反应长期以来一直被证明是至关重要的。 对球孢子菌感染有有效的免疫力。我们最近确定，无法解决球孢子菌 感染可能是调节性T细胞频率和功能能力升高结果，且调节性T 细胞频率可以预测诊断时患者的疾病结果。我们建议：1）定义表型， 球孢子菌感染患者在疾病早期的调节性T细胞功能，以及2）确定 可用于诊断的生物标记算法，用于校准这些患者的治疗积极性 最有可能发展为慢性球孢子菌病。该项目的成功完成将为 诊断工具，以在病程早期识别患者，进行更积极的治疗， 监测治疗后的复发，并将更好地定义慢性疾病的免疫机制。 球虫病

PROJECT SUMMARY Coccidioidomycosis, known as Valley fever, is caused by the fungal pathogen (Coccidioides) endemic to the San Joaquin Valley in California, Arizona, northern Mexico and arid areas of South America. Incidence in California is on the rise, and there is evidence indicating that the disease can be found in non-endemic regions including Washington State. Population expansion, travel, detection and/or weather changes appear to be contributing to an expanding endemic region. The health impacts of Valley fever infection can range from superficial to lethal. For the 60% of people who are infected, but do not display symptoms of Valley fever, the impact of the disease is likely to be minimal. For the 40% of symptomatic patients, most will display symptoms similar to the flu and the condition will resolve without treatment. Nevertheless, these patients can experience significantly impaired health for a lengthy period of time. For 1% of the patients, Valley fever results in a severe or prolonged clinical illness with dramatic health impacts, including chronic pulmonary nodules or cavities, with the potential for misdiagnosis, and even death. Disease is often misdiagnosed as a bacterial infection, often resulting in several rounds of antibiotic treatments before a correct diagnosis. The health impacts of Valley fever infection thus vary dramatically, and little is known about the biological factors that influence the severity of symptoms and health complications experienced following infection. Although the details are still unclear, cellular immune responses have long been shown to be critical for effective immunity to Coccidioides infection. We recently determined that the inability 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. We propose to: 1) define the phenotype and function of regulatory T cells in Coccidioides infected patients during early disease, and 2) to define a biomarker algorithm that can be used at diagnosis for calibrating treatment aggressiveness for those patients most likely to develop chronic cocciodiomycosis. The successful completion of this project will provide diagnostic tools to identify patients earlier in their disease course for more aggressive treatment and closer monitoring for relapse after treatment, and will better define the immune mechanisms underlying chronic cocciodiomycosis.