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.

抽象的 播散性球孢子菌病 (DCM) 可以通过宿主防御缺陷和 真菌成功逃避免疫。我们实验室发布的数据强调了 T 细胞在 对抗真菌感染，并避免传播疾病。我们的主要目标是发现 T 细胞 介导功能障碍并允许侵袭性球孢子菌病的模式和程序。 T 细胞激活需要呈递病原体抗原，这个过程提供了 创始人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 HLA 等位基因，已被证明在严重感染的易感性中发挥重要作用，包括 球孢子菌病，因为这些分子向 T 细胞呈递抗原肽。哪些 HLA 等位基因有贡献 20 多年来一直没有对易感性进行研究，现代方法，包括由 我们的团队对抗原呈递过程有了更多的了解。重要的是，哪些肽是 对于预防球孢子菌病的重要性尚不清楚。我们的方法数据包含一项新技术 凭经验发现球孢子菌的那些关键肽。在目标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，在抗原呈递细胞的细胞因子的提示下出现转录程序。 我们发表的初步数据支持 T 细胞功能障碍是免疫反应缺陷的基础 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血统相关的单倍型变异造成的。 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偏差所致。清除 几天内消灭病原体是必要的，否则持续的抗原暴露会导致 T 细胞陷入严重的死亡状态。 表型转换，包括物理消除抗原特异性 T 细胞，驱使它们进入抗原状态 反应迟钝，或使他们进入衰老状态。我们的初步数据支持在受试者中 DCM 中，T 细胞同时表现出衰竭和衰老表型。在目标 2 中，我们将首先采取无偏见的 发现突出 DCM 与 UVF 的转录模式的方法。我们将追求单细胞RNA- seq 和 scATAC-seq 来识别与疾病相关的细胞和转录模式。我们将学习 使用这种方法，患有扩张型心肌病的受试者具有上述三种功能失调程序的标记。这些 研究将能够发现 DCM 患者的各个亚类及其功能缺陷 T细胞。