Integrated Multi-omics of Melioidosis

类鼻疽的综合多组学

• 批准号: 9978698
• 负责人: Sina A Gharib
• 金额: $ 86.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-23 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978698
• 关键词: Acute Pneumonia; Address; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bioinformatics; Biological; Biological Process; Blood; Blood specimen; Burkholderia pseudomallei; Candidate Disease Gene; Cells; Cessation of life; Clinical; Collaborations; Communities; Complement; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Early identification; Environmental Exposure; Exposure to; Genes; Genetic Determinism; Genetic Transcription; Genetic Variation; Host Defense Mechanism; Human; Human Genetics; Immune; Immune response; Immunotherapy; In Vitro; Infection; Inflammatory Response; Ingestion; Inhalation; Investigation; Knowledge; Leukocytes; Measures; Melioidosis; Messenger RNA; Metabolic Pathway; MicroRNAs; Molecular; Molecular Profiling; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Plasma; Play; Predisposition; Process; Proteins; Proteomics; Public Health; Research; Research Personnel; Resources; Risk; Role; Sepsis; Soil; Technology; Testing; Therapeutic; Vaccine Design; Vaccines; Work; adverse outcome; aptamer; base; combat; computer framework; differential expression; exome sequencing; experience; experimental study; high risk; improved; in vitro Assay; in vivo Model; innovation; interest; metabolomics; mortality; multidimensional data; multiple omics; neglect; new therapeutic target; next generation; novel; novel strategies; outcome forecast; peripheral blood; predictive signature; prevent; prognostic; prognostic signature; septic patients; tool; transcriptome sequencing; transcriptomics; vaccine development

PROJECT SUMMARY Melioidosis, a tropical infection commonly manifesting as acute pneumonia and sepsis in humans, is caused by the Gram-negative Tier 1 select agent Burkholderia pseudomallei and represents a global public health threat with an estimated 165,000 cases and 89,000 deaths annually worldwide (an overall mortality rate of 54%). Unfortunately numerous barriers exist to decreasing the burden of melioidosis including lack of an effective vaccine, difficulty diagnosing and identifying high-risk patients, and challenges in treatment due to extensive antimicrobial resistance of B. pseudomallei and lack of targeted immunotherapies. While work to date spotlights the promise of the application of advanced technologies to melioidosis and identifies several targets for further study, an incomplete understanding of the pathogenic mechanisms underlying host susceptibility and outcome impedes efforts to prevent, diagnose, risk-stratify and treat this infection. The overall hypothesis of this project is that by generating and integrating a rich compendium of multidimensional data – transcriptomic, proteomic, and metabolomic – from circulating immune cells and blood of patients with melioidosis and selected controls, it is possible to identify fundamental biological pathways and processes activated during melioidosis. Such comprehensive data, complemented by targeted in vitro experiments, are desperately needed to inform the design of vaccines, diagnostics, prognostics and therapeutics to combat this infectious threat. This hypothesis will be tested in the following aims: 1) Identify biological pathways that distinguish melioidosis from other causes of sepsis; 2) Define biological processes and develop prognostic signatures that predict death in melioidosis; and 3) Validate the function of key genes and pathways in human cells infected with B. pseudomallei in vitro. This application leverages the investigators’ scientific and clinical expertise in melioidosis, cutting edge bioinformatics capacity in transcriptomics, proteomics, and metabolomics both as independent domains and integrated together, and a rich clinical and biological dataset of over 5,000 septic patients due to melioidosis or to other infections. The successful completion of this project will yield an unprecedented granular overview of mechanisms leading to melioidosis and the molecular signatures associated with clinical outcomes, while also providing a unique resource to the scientific community to guide further research into this important but neglected disease.

项目概要 类鼻疽是一种热带感染，通常表现为人类急性肺炎和败血症，由类鼻疽引起 由革兰氏阴性 1 级选择病原体拟鼻疽伯克霍尔德菌 (Burkholderia pseudomallei) 产生，代表了全球公共卫生 全球每年估计有 165,000 例病例和 89,000 人死亡（总死亡率 54%）。不幸的是，减轻类鼻疽负担存在许多障碍，包括缺乏 有效的疫苗、高危患者的诊断和识别困难以及治疗方面的挑战 鼻疽伯克氏菌广泛的抗菌耐药性和缺乏靶向免疫疗法。在工作的同时 日期强调了先进技术应用于类鼻疽的前景，并确定了一些 进一步研究的目标，对宿主致病机制的不完全了解 易感性和结果阻碍了预防、诊断、风险分层和治疗这种感染的努力。这 该项目的总体假设是，通过生成和整合丰富的多维概要 数据——转录组学、蛋白质组学和代谢组学——来自患有以下疾病的患者的循环免疫细胞和血液 类鼻疽和选定的对照，可以确定基本的生物学途径和过程 类鼻疽期间被激活。这些全面的数据，加上有针对性的体外实验， 迫切需要为疫苗、诊断、预后和治疗的设计提供信息以应对这一问题 传染性威胁。该假设将在以下目标中得到检验：1）确定生物途径 区分类鼻疽与脓毒症的其他原因； 2) 定义生物过程并制定预后 预测类鼻疽死亡的特征； 3) 验证人类关键基因和通路的功能 体外感染类鼻疽杆菌的细胞。该应用程序利用了研究人员的科学和临床能力 类鼻疽方面的专业知识、转录组学、蛋白质组学和代谢组学方面的尖端生物信息学能力 既是独立的领域又是集成在一起的，以及超过 5,000 个丰富的临床和生物学数据集 由于类鼻疽或其他感染引起的脓毒症患者。该项目的顺利完成将产生 对导致类鼻疽的机制和分子特征进行了前所未有的细致概述 与临床结果相关，同时还为科学界提供独特的资源来指导 对这一重要但被忽视的疾病的进一步研究。