T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

T 细胞功能障碍是播散性球孢子菌病的基础

基本信息

批准号：
10338193
负责人：
MANISH J BUTTE
金额：
$ 22.32万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-02 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338193
关键词：
Acute Aftercare Agricultural Workers Antifungal Agents Antigens Biological Markers Blocking Antibodies California Cell Differentiation process Cells Child Clinic Clinical Clinical Trials Coccidioides Coccidioidomycosis Collaborations Communicable Diseases Data Defect Development Disease Early identification Exposure to FDA approved Failure Functional disorder Future GTP-Binding Protein alpha Subunits, Gs Genetic Genetic Risk Genetic Transcription Genome Goals Grant Helper-Inducer T-Lymphocyte Hospitalization Host Defense Human IL4 gene Immune Immune System Diseases Immune response Immunity Immunogenetics Immunologics Immunologist Immunomodulators Impairment In Vitro Individual Infection Institutes Interferon Type II Interleukin 4 Receptor Interleukin-13 Interleukin-4 Journals Lead Life Light Lung diseases Lung infections Medicine Memory Meningitis Military Personnel Mus Mutation Mycoses New England Outcome Paper Pathway interactions Patient Care Patients Pattern Persons Pharmaceutical Preparations Phase Phenotype Predisposition Prisoner Production Publishing RNA Splicing Risk Sampling Signal Transduction T cell response T memory cell T-Lymphocyte Testing Time Ursidae Family Variant Work adaptive immune response base clinical practice cytokine desert fever effective therapy exon skipping fungus genomic biomarker high risk immunomodulatory therapies innovation inter-individual variation interleukin-12 receptor interleukin-13 receptor mortality phenotypic biomarker programs prophylactic response screening transcriptome

项目摘要

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.

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为什么有些人会患上扩张型心肌病，而另一些人会患上轻微的肺部疾病（“谷热”），或者 DCM 尚无有效治疗方法，患者必须存活下来。因此，迫切需要更好地了解 DCM 并更好地进行治疗。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 型免疫的免疫遗传学程序） 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，我们在该病例中表明 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 细胞功能障碍如果证实，Th 会引起很大一部分患者发展为扩张型心肌病 (DCM)。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 DCM 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，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—— 我们的工作还将为预测 DCM 的易感性奠定遗传基础。此外，我们将在体外展示两种 FDA 批准的药物的能力。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。