T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

项目概要/摘要 播散性球孢子菌病（DCM）是一种罕见的，但危及生命的后果感染的 球孢子菌为什么有些人会得DCM，而另一些人会得轻度肺病（“山谷热”）， 是否仍无症状尚不清楚。DCM没有有效的治疗方法，存活的患者必须 终生服用抗真菌药因此，迫切需要更好地了解DCM， 治疗。 基于人类和小鼠免疫学家数十年的工作，我们认为宿主对 球孢子菌在DCM中是有缺陷的，其中心是辅助性T细胞产生干扰素γ（IFN-γ）的失败。 细胞（称为1型免疫的免疫遗传程序）。1型免疫在免疫系统中的重要性 对球孢子菌的反应进一步证明了我们所描述的DCM患者，亚形态功能 IL-12受体，和Th 1分化的严重缺陷。在这个案例中，我们证明了DCM可以被清除， 在用IFN-γ和临床可用的IL-4受体阻断抗体进行创新治疗后。 总之，我们的初步和已发表的数据支持Th细胞功能障碍的中心假设， 在很大一部分患者中引起扩张型心肌病的发展。如果被证实，筛查Th 功能障碍和IFN-γ和IL-4受体阻断治疗可以挽救这些遗传扰动， 为扩张型心肌病提供治疗为了研究扩张型心肌病的免疫反应，我们组建了一个免疫学家团队， 遗传学家和加州大学洛杉矶分校的感染专家，并与山谷热研究所（VFI）合作， 加州最大的球孢子菌诊所，提供DCM和单纯性山谷热（UVF）的样本。 我们的目标包括：1）识别2型偏态DCM患者及其遗传基础; 发现DCM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这种生命的高效治疗方法- 威胁真菌感染我们的工作还将建立一个预测DCM易感性的遗传基础， 可以在未来的工作中进行测试。此外，我们将在体外证明两种FDA批准的药物 扭曲记忆T细胞对球孢子菌的反应，代表了临床试验的第一步， 为一种无法治愈的疾病建立新的治疗方法。

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.