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: 10554381
• 负责人: MANISH J BUTTE
• 金额: $ 19.88万
• 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/10554381
• 关键词: ATAC-seq; Alleles; Antigen Presentation; 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; Variant; Virulence; Work; adaptive immunity; antigen-specific T cells; cytokine; desert fever; exhaustion; fighting; fungus; genetic variant; high dimensionality; immunogenic; new technology; pathogen; phenotypic data; premature; programs; receptor; 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.

摘要 播散性球孢子菌病(DCM)可由宿主防御缺陷和 这种真菌成功地逃避了免疫。我们实验室公布的数据强调了T细胞在疾病中的重要性 与真菌感染作斗争，并在传播疾病中出错。我们的主要目标是发现T细胞 调节功能障碍并允许侵袭性球孢子菌病的模式和程序。 T细胞的激活需要呈现病原体的抗原，这一过程提供了一种 创立者获得适应性免疫的机会。主要组织相容性复合体(MHC)亚型，通常也 被称为人类白细胞抗原的等位基因，已被证明在严重感染的易感性中起着重要作用，包括 球孢子菌病，因为这些分子向T细胞呈递抗原肽。哪些人类白细胞抗原等位基因有贡献 对易感性的研究已经有20多年了，现代方法，包括那些由 我们的团队对抗原呈递过程有了更多的了解。重要的是，哪些多肽是 对球孢子菌病的重要保护作用尚不清楚。我们的方法数据包括一项新技术 经验性地发现球虫的那些关键多肽。在目标1中，我们将发现抗原肽， 以及介导扩张型心肌病的T细胞受体。 当T细胞激活时，在抗原提呈细胞的细胞因子的提示下，转录程序出现。 我们发表的和初步的数据支持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引起的， 这可能是由于罕见或常见的遗传变异或与遗传祖先相关的单倍型变异所致。 这些异常反应也可能是由于APC产生的细胞因子引起的异常倾斜。净空 在几天内发现病原体是必要的，否则持续的抗原暴露将使T细胞 一种表型转换，包括物理消除抗原特异性T细胞，将它们驱动到抗原状态- 没有反应，或者将他们推向衰老的状态。我们的初步数据支持这一点 DCM，T细胞既有衰竭表型，又有衰老表型。在目标2中，我们将首先不偏不倚地 发现突出DCM和UVF的转录模式的方法。我们将追求单细胞核糖核酸- SEQ和scATAC-seq用于识别与疾病相关的细胞和转录模式。我们会研究 具有上述三种功能障碍标志的扩张型心肌病患者采用这种方法。这些 研究将能够发现扩张型心肌病患者的各种亚类以及他们的功能缺陷 T细胞。