Adaptive Immune Dysregulation in Disseminated Coccidioidomycosis

播散性球孢子菌病的适应性免疫失调

• 批准号: 10356729
• 负责人: MANISH J BUTTE
• 金额: $ 24.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356729
• 关键词: ATAC-seq; Alleles; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Automobile Driving; Binding; COVID-19; Catalogs; Cells; Coccidioides; Coccidioidomycosis; Cues; Cytometry; Data; Defect; Disease; Epigenetic Process; Epitopes; Exhibits; Functional disorder; Genetic; Genetic Transcription; Genome; Genomics; Goals; Haplotypes; Helper-Inducer T-Lymphocyte; Host Defense; Immune; Immune Evasion; Immune response; Immunogenetics; Individual; Infection; Light; Major Histocompatibility Complex; Measures; Mediating; Modernization; Mus; Mycoses; Pathway interactions; Patients; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Play; Predisposition; Process; Publishing; Reagent; Regulator Genes; Role; Severity of illness; Signal Transduction; Study Subject; Subcategory; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Ursidae Family; Variant; Virulence; Work; adaptive immunity; antigen-specific T cells; base; cytokine; desert fever; exhaustion; fighting; fungus; genetic variant; high dimensionality; immunogenic; new technology; pathogen; phenotypic data; premature; programs; response; senescence; single cell sequencing; single-cell RNA sequencing; tool; transcriptome; transcriptomics; ATAC-seq; Alleles; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Automobile Driving; Binding; COVID-19; Catalogs; Cells; Coccidioides; Coccidioidomycosis; Cues; Cytometry; Data; Defect; Disease; Epigenetic Process; Epitopes; Exhibits; Functional disorder; Genetic; Genetic Transcription; Genome; Genomics; Goals; Haplotypes; Helper-Inducer T-Lymphocyte; Host Defense; Immune; Immune Evasion; Immune response; Immunogenetics; Individual; Infection; Light; Major Histocompatibility Complex; Measures; Mediating; Modernization; Mus; Mycoses; Pathway interactions; Patients; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Play; Predisposition; Process; Publishing; Reagent; Regulator Genes; Role; Severity of illness; Signal Transduction; Study Subject; Subcategory; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Ursidae Family; Variant; Virulence; Work; adaptive immunity; antigen-specific T cells; base; cytokine; desert fever; exhaustion; fighting; fungus; genetic variant; high dimensionality; immunogenic; new technology; pathogen; phenotypic data; premature; programs; response; senescence; single cell sequencing; single-cell RNA sequencing; tool; transcriptome; transcriptomics

Abstract Disseminated coccidioidomycosis (DCM) can be explained by a combination of defective host defenses and successful immune evasion by the fungus. Published data from our labs highlight the importance of T cells in fighting fungal infections, and in going awry in disseminated disease. Our main goal is to discover the T cell patterns and programs that mediate dysfunction and allow for invasive coccidioidomycosis. T-cell activation requires the antigens of the pathogen to be presented, and this process offers an opportunity for adaptive immunity to founder. Major histocompatibility complex (MHC) subtypes, commonly also called HLA alleles, have been shown to play an important role in susceptibility to severe infection, including coccidioidomycosis, because these molecules present antigenic peptides to T cells. Which HLA alleles contribute to susceptibility has not been studied in over 20 years, and modern approaches including those published by our team shed considerably more light on the antigen presentation process. Importantly, which peptides are important for protection to coccidioidomycosis is as yet unknown. Our approach data includes a new technology to empirically discover those key peptides of Coccidioides. In Aim 1, we will discover the antigenic peptides, HLAs, and T-cell receptors that mediate DCM. Upon T-cell activation, transcriptional programs arise as cued by cytokines of the antigen presenting cells. Our published and preliminary data support that T-cell dysfunction underlies the defective immune responses of DCM. These aberrant responses may arise either due to genetic or epigenetic defects of the T cell program, which may be due to rare or common genetic variants or haplotype variants associated with genetic ancestry. These aberrant responses could also be due to abnormal skewing due to cytokines made by APCs. Clearance of pathogens within a few days is requisite, or else persistent antigen exposure drives T cells to a profound phenotypic switch that includes physical elimination of antigen-specific T cells, driving them to a state of antigen- unresponsiveness, or driving them to a state of senescence. Our preliminary data support that in subjects with DCM, T cells exhibit both an exhaustion and senescence phenotype. In Aim 2, we will first take an unbiased approach to discover transcriptional patterns that highlight DCM versus UVF. We will pursue single-cell RNA- seq and scATAC-seq to identify cells and patterns of transcription that correlate with disease. We will study subjects with DCM who bear the markers of the three dysfunctional programs above with this approach. These studies will enable discovery of the various subcategories of DCM patients and the functional deficiencies in their T cells.

抽象的 传播的球菌病（DCM）可以通过有缺陷的宿主防御和 真菌成功逃避免疫。来自我们实验室的数据突出了T细胞在 与真菌感染作斗争，并在传播疾病中出现问题。我们的主要目标是发现T细胞 介导功能障碍并允许侵入性球菌病的模式和程序。 T细胞激活需要呈现的病原体的抗原，此过程提供了一个 适应性免疫的机会。主要的组织相容性复合物（MHC）亚型，通常也 称为HLA等位基因，已被证明在严重感染的易感性中起着重要作用，包括 球虫菌病，因为这些分子对T细胞呈现抗原肽。哪个HLA等位基因贡献 为了使易感性尚未在20多年中研究，现代方法在内 我们的团队对抗原演示过程更加明显。重要的是，哪种肽是 对于保护球菌病的保护很重要，尚不清楚。我们的方法数据包括一项新技术 从经验上发现球虫剂的那些关键肽。在AIM 1中，我们将发现抗原肽， HLA和介导DCM的T细胞受体。 T细胞激活后，转录程序是由抗原呈递细胞的细胞因子提出的。 我们已发布和初步数据支持T细胞功能障碍是有缺陷的免疫反应的基础 DCM。这些异常反应可能是由于T细胞程序的遗传或表观遗传缺陷而产生的， 这可能是由于与遗传血统相关的罕见或常见的遗传变异或单倍型变异。 这些异常反应也可能是由于APC的细胞因子引起的异常偏斜。清除 几天之内的病原体是必需的 表型开关包括物理消除抗原特异性T细胞，将其驱动到抗原状态 反应迟钝，或者将它们带到衰老状态。我们的初步数据支持的主题 DCM，T细胞既表现出疲惫和衰老表型。在AIM 2中，我们将首先采取公正 发现突出显示DCM与UVF的转录模式的方法。我们将追求单细胞RNA- SEQ和SCATAC-SEQ鉴定与疾病相关的细胞和转录模式。我们将学习 具有DCM的受试者，他们以这种方法具有上面三个功能失调程序的标记。这些 研究将使DCM患者的各种子类别以及其功能性缺陷在其中发现 T细胞。