T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

项目概要/摘要 播散性球孢子菌病 (DCM) 是一种罕见但危及生命的感染后果 真菌球孢子菌。为什么有些人会患 DCM，而另一些人会患轻度肺部疾病（“谷热”），或者 是否仍无症状尚不清楚。 DCM 尚无有效治疗方法，存活下来的患者必须 终生服用抗真菌药物。因此，迫切需要更好地了解DCM并更好地了解DCM。 治疗。 根据人类和小鼠免疫学家数十年的工作，我们相信宿主的免疫反应 球孢子菌在扩张型心肌病中存在缺陷，其核心是辅助 T 无法产生干扰素-γ (IFN-ɣ) 细胞（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 我们所描述的患有扩张型心肌病（DCM）的患者进一步证明了对球孢子菌的反应，功能低下 IL-12 受体的缺失，以及 Th1 分化的严重缺陷。我们在这个案例中证明了 DCM 可以被清除 采用 IFN-ɣ 和临床可用的 IL-4 受体阻断抗体进行创新治疗后。 我们的初步数据和已发表的数据共同支持了以下中心假设：Th 细胞功能障碍 引起很大一部分患者发展为 DCM。如果证实有效，则筛查 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 提供 DCM 的治疗。为了研究 DCM 的免疫反应，我们组建了一个免疫学家团队， 加州大学洛杉矶分校的遗传学家和感染专家，并与 Valley Fever Institute (VFI) 合作， 加利福尼亚州最大的球孢子菌诊所，提供 DCM 和简单的谷热 (UVF) 样本。 我们的目标包括 1) 识别患有 DCM 的 2 型偏态个体及其遗传基础； 2) 发现 DCM 中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今生的高效治疗方法—— 威胁真菌感染。我们的工作还将建立预测 DCM 易感性的遗传基础 可以在以后的工作中进行检验。此外，我们将在体外展示两种 FDA 批准药物的能力 扭曲记忆 T 细胞对球孢子菌的反应，这是迈向临床试验的第一步， 为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.