Immune and metabolic correlates of Coccidioides disease spectrum and outcomes

球孢子菌疾病谱和结果的免疫和代谢相关性

• 批准号: 10364969
• 负责人: Satya Dandekar
• 金额: $ 37.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364969
• 关键词: Acute; Antibodies; Bacterial Infections; Biological Markers; Blood specimen; Body Fluids; Cell physiology; Cerebrospinal Fluid; Chronic lung disease; Clinical; Clinical assessments; Coccidioides; Coccidioidomycosis; Data; Data Analyses; Databases; Development; Diagnostic; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Enrollment; Eosinophilia; Epitope Mapping; Failure; Future; Goals; Immune; Immune System Diseases; Immune response; Immunity; Immunologics; Impairment; In Vitro; Individual; Infection; Integration Host Factors; Interdisciplinary Study; Investigation; Knowledge; Laboratories; Lung diseases; Maps; Measurement; Measures; Meningitis; Metabolic; Metabolic Pathway; Metabolic dysfunction; Molecular; Monitor; Morbidity - disease rate; Newly Diagnosed; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Prospective Studies; Pulmonary Pathology; Resources; Role; Sampling; Severities; Severity of illness; Stream; Symptoms; T cell response; Therapeutic; Time; Treatment Failure; Virus Diseases; base; biosignature; clinical care; clinical diagnostics; cohort; data resource; desert fever; experience; high risk; in vivo; lung development; macrophage; metabolomics; mortality; mouse model; mutant; pathogen; peripheral blood; process evaluation; prognostic; repository; research clinical testing; sample collection; targeted treatment; therapeutic target; transcriptomics

Coccidioides infection leads to acute or chronic pulmonary disease (Valley Fever) with a wide spectrum of disease severity. However, the mechanisms of coccidioidomycosis severity and therapeutic failures are not fully elucidated and correlates of disseminated or unresolved infection are not well established. The overall objective of Project 3 is to investigate the immune and metabolic correlates of Coccidioides infection and disease spectrum and to identify mechanisms of disease pathogenesis. Our preliminary data of immune responses and metabolomic profiles in samples from patients infected with Coccidioides identified the metabolic signature of key dysregulated pathways. We hypothesize that Coccidioides infection-induced metabolic changes reflecting the major dysregulated host cellular pathways can predict disease severity and clinical outcomes. We propose to build on our collective strengths in coccidioidomycosis diagnostics and clinical care of large patient cohorts with Coccidioides infection at UC Davis to determine the pathogenic mechanisms of coccidioidomycosis and to investigate a prognostic biosignature that can identify the future course of disease progression. This project leverages the availability of clinical sample collection from patients with coccidioidomycosis and database, resources from the existing Centers, technical and scientific knowledge of immunological and metabolic analyses, mouse models of coccidioidomycosis, strong preliminary data and a multi-disciplinary research team. There are three specific aims. Aim 1: To determine immune and metabolic correlates of the disease spectrum and infection outcomes and identify pathways for therapeutic targeting. Longitudinal samples from newly diagnosed patients with Coccidioides at UC Davis will be evaluated for immune and metabolic changes and the key dysregulated cellular/metabolic pathways and correlates of disease outcomes will be identified. Aim 2: To identify immune and metabolic correlates of treatment failures and determine mechanisms contributing to this treatment failure. Disseminated Coccidioides infection with severe disease is associated with morbidity/mortality. Clinical samples from patients with disseminated Coccidioides receiving clinical care at UC Davis will be enrolled in this prospective study. Aim 3: To investigate the pathogenic determinants of Coccidioides that promote induction of immune and metabolic dysfunction and lung pathology in vivo. We will utilize the mouse model of coccidioidomycosis to investigate the development of lung pathology, eosinophilia and metabolic dysregulation by Coccidioides wild-type and mutant strains and map the pathogenic determinants. An integrated analysis will be performed of host responses to Coccidioides in vivo through clinical (Project 3), metabolic (Project 3) and transcriptomic (Project 2) data and to Coccidioides mutant strains in vitro and in the mouse model (Core 3, Projects 1 and 2) Collectively, our proposed studies will (a) fill the gaps in our understanding of the role of both pathogenic determinants and host factors contributing to the disease spectrum of Valley Fever and (b) identify potential correlates of disease outcomes and targets for therapy.

球球菌的感染导致急性或慢性肺部疾病（Valley Fever）具有广泛的光谱 疾病严重程度。然而，球虫菌病严重程度和治疗失败的机制不是 完全阐明和未分辨感染的完全阐明和相关性尚未得到很好的确定。总体 项目3的目的是研究球虫下感染和疾病的免疫和代谢相关性 光谱并确定疾病发病机理的机制。我们免疫反应的初步数据和 感染了球虫剂的患者样品中的代谢组学特征，确定了的代谢特征 钥匙失调的途径。我们假设球虫下感染引起的代谢变化反映了 主要失调的宿主细胞途径可以预测疾病的严重程度和临床结果。我们建议 建立我们在球虫菌病诊断的集体优势和大型患者队列的临床护理 加州大学戴维斯加州大学的球虫下感染，以确定球虫病的致病机制和TO 研究可以识别未来疾病进展过程的预后生物签名。这个项目 利用球虫病和数据库患者的临床样本收集可用性， 现有中心的资源，免疫和代谢的技术和科学知识 分析，球虫病的小鼠模型，强大的初步数据和多学科研究小组。 有三个特定的目标。目标1：确定疾病的免疫和代谢相关性 频谱和感染结果并确定治疗靶向的途径。纵向样本 戴维斯分校的新诊断为Coccidioides的患者将接受免疫和代谢变化的评估 将确定关键调节的细胞/代谢途径和疾病结局的相关性。目的 2：确定治疗失败的免疫和代谢相关性，并确定有助于 这种治疗失败。传播的球虫剂感染患有严重疾病 发病率/死亡率。来自UC的临床护理的散布coccidioides患者的临床样本 戴维斯将参加这项前瞻性研究。目标3：研究的病原决定因素 促进体内免疫和代谢功能障碍和肺病理学的球球菌。我们将 利用球虫的小鼠模型研究肺病理学，嗜酸性粒细胞病的发展 球虫型野生型和突变菌株的代谢失调，并绘制致病性决定因素。 将通过临床（项目3），对体内球球菌的宿主反应进行综合分析。 代谢（项目3）和转录组（项目2）数据以及在体外和在 鼠标模型（核心3，项目1和2）集体，我们的拟议研究将（a）填补我们的空白 了解导致疾病谱系的病原决定因素和宿主因素的作用 山谷热和（b）确定疾病结局和治疗靶标的潜在相关性。