T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

项目摘要/摘要 播散性球孢子菌病(DCM)是一种罕见的但危及生命的感染后果，由 球孢子菌。为什么有些人得了DCM，有些人得了轻微的肺部疾病(“谷热”)，或者 目前尚不清楚是否有无症状。目前还没有有效的治疗DCM的方法，存活下来的患者必须 终身服用抗真菌药物。因此，迫切需要更好地了解DCM和更好地 治疗。 基于人类和小鼠免疫学家数十年的研究，我们认为宿主对 球虫类药物在扩张型心肌病中有缺陷，主要是辅助T细胞产生干扰素-ɣ失败 细胞(一种称为1型免疫的免疫遗传程序)。1型免疫在免疫中的重要性 我们描述的一位患有DCM的患者--亚形态功能--进一步证明了对球虫类药物的反应 IL-12受体，以及Th1分化的严重缺陷。在这种情况下，我们展示了DCM可以被清除 经过干扰素-ɣ和一种临床可用的IL-4受体封闭抗体的创新治疗。 总之，我们的初步和已发表的数据支持Th细胞功能障碍这一中心假设 在相当一部分患者中引发DCM的发展。如果被证实，筛查Th 功能障碍和干扰素-γ和IL-4受体阻断治疗可以挽救这些遗传紊乱和 为扩张型心肌炎提供治疗方法。为了研究DCM的免疫反应，我们组建了一个免疫学家团队， 来自加州大学洛杉矶分校的遗传学家和感染专家，并与山谷发烧研究所(VFI)合作 加州最大的球孢子虫诊所，提供DCM和单纯谷热(UVF)的样本。 我们的目标包括1)识别患有DCM的2型偏斜个体及其遗传基础； 2)发现扩张型心肌病免疫功能障碍的转录模式和途径。 这项工作的总体影响是加速寻找针对此生的高效治疗方法- 有真菌感染的危险。我们的工作还将建立预测DCM易感性的遗传学基础 可以在以后的工作中检验。此外，我们将在体外演示两种FDA批准的药物的能力 扭曲记忆T细胞对球虫的反应，这是迈向临床试验的第一步， 为一种不治之症建立一种新的治疗方法。

PROJECT SUMMARY/ABSTRACT Disseminated coccidioidomycosis (DCM) is an uncommon but life-threatening consequence of infection by the fungus Coccidioides. Why some people get DCM and others a mild pulmonary disease (“Valley Fever”), or remain asymptomatic is unknown. There are no effective treatments for DCM, and patients who survive must remain on antifungals for life. Thus, there is an urgent need for a better understanding of DCM and for better treatments. Based on decades of work by human and mouse immunologists, we believe the host's immune responses to Coccidioides are defective in DCM and center on a failure of interferon-gamma (IFN-ɣ) production by helper T cells (an immunogenetic program called Type-1 immunity). The importance of Type-1 immunity in the immune response to Coccidioides is further evidenced by a patient we have described with DCM, hypomorphic function of the IL-12 receptor, and a severe defect in Th1 differentiation. We showed in this case that DCM could be cleared after innovative treatment with IFN-ɣ and a clinically-available blocking antibody of IL-4 receptor. Together, our preliminary and published data support the central hypothesis that Th cell dysfunction provokes the development of DCM in a significant fraction of patients. If proven out, screening for Th dysfunction and treatment with IFN-γ and IL-4 receptor blockade could rescue these genetic perturbations and offer a treatment for DCM. To study the immune response in DCM, we have assembled a team of immunologists, geneticists, and infection experts from UCLA, and have partnered with the Valley Fever Institute (VFI), the largest Coccidioides clinic in California, to provide samples from DCM and uncomplicated Valley Fever (UVF). Our Aims include 1) Identify type-2 skewed individuals with DCM and their genetic underpinnings; and 2) Discover transcriptional patterns and pathways of immune dysfunction in DCM. The overall impact of this work is to accelerate the search for highly effective treatments for this life- threatening fungal infection. Our work will also establish a genetic basis for predicting susceptibility to DCM that can be tested in future work. Additionally, we will demonstrate in vitro the ability of two FDA-approved drugs to skew memory T cell responses against Coccidioides, representing the first steps towards a clinical trial and the establishment of a new treatment for an otherwise incurable disease.