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

• 批准号: 10226751
• 负责人: MANISH J BUTTE
• 金额: $ 19.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226751
• 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; 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

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.

项目摘要/摘要 传播球菌病（DCM）是一种罕见但威胁生命的后果。 真菌球虫剂。为什么有些人患DCM，而其他人则患有轻度肺部疾病（“山谷热”）或 保持不对称是未知的。 DCM没有有效的治疗方法，生存的患者必须 保持抗真菌的生命。那迫切需要更好地理解DCM并更好地理解 治疗。 根据人和老鼠免疫学家数十年的工作，我们认为宿主的免疫调查会给 球球菌剂在DCM中有缺陷，并以助手T的干扰素 - 伽马（IFN-ɣ）失败为中心 细胞（一种称为1型免疫的免疫原性程序）。 1型免疫在免疫中的重要性 我们已经描述了DCM的患者进一步证明了对球虫剂的反应 IL-12受体和Th1分化的严重缺陷。在这种情况下，我们表明DCM可以清除 在使用IFN-ɣ和IL-4受体的临床可用抗体进行创新治疗后。 我们的初步和发布的数据一起支持了细胞功能障碍的中心假设 在很大一部分患者中挑衅DCM的发展。如果证明了，请筛选 IFN-γ和IL-4受体阻滞的功能障碍和治疗可以挽救这些遗传扰动和 为DCM提供治疗。为了研究DCM中的免疫响应，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仿制药和感染专家，并与Valley Fever Institute（VFI）合作 加利福尼亚州最大的球虫诊所，可提供DCM和简单谷热（UVF）的样品。 我们的目标包括1）确定具有DCM及其遗传基础的2型偏斜个体； 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这一生的高效治疗方法 - 威胁真菌感染。我们的工作还将建立一个遗传基础，以预测对DCM的易感性 可以在以后的工作中进行测试。此外，我们将在体外演示两种FDA批准的药物的能力 将记忆T细胞反应偏向与球椰子菌的反应，代表了临床试验的第一步和 建立针对原本无法治愈的疾病的新疗法。