Multi-omics of murine respiratory melioidosis

小鼠呼吸道类鼻疽的多组学

• 批准号: 10724512
• 负责人: Sina A Gharib
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724512
• 关键词: Admission activity; Animal Model; Antibiotic Therapy; Aromatherapy; Bacteremia; Bioinformatics; Biological; Bioterrorism; Blood; Burkholderia pseudomallei; Cells; Cessation of life; Classification; Data; Disease; Disease Outbreaks; E. coli bacteremia; Environment; Experimental Models; Failure; Genetic Transcription; Goals; Heterogeneity; Hospitalization; Host Defense; Host Defense Mechanism; Hour; Human; Immune response; Infection; Ingestion; Inhalation; Investigation; Klebsiella pneumoniae; Knowledge; Leukocytes; Lung; Melioidosis; Mississippi; Multiomic Data; Mus; Outcome; Overlapping Genes; Pathway interactions; Patients; Phenotype; Plasma; Pneumonia; Prospective cohort; Proteomics; Public Health; Resolution; Resources; Respiratory Tract Infections; Route; Sampling; Sepsis; Signal Transduction; Soil; Staphylococcus aureus; Structure of parenchyma of lung; Thailand; Time; United States; case control; clinically relevant; comparative; disease phenotype; human disease; improved; insight; lung failure; metabolome; metabolomics; mortality; mortality risk; mouse model; multiple omics; novel; pathogen; peripheral blood; programs; recruit; respiratory; single nucleus RNA-sequencing; success; targeted treatment; transcriptome; transcriptomics

PROJECT SUMMARY Melioidosis is an often-fatal infection caused by inhalation, inoculation, or ingestion of the Gram-negative facultative intracellular pathogen and Tier 1 select agent Burkholderia pseudomallei (Bps). Bps has recently been isolated from the soil in the southern United States. Worldwide, 165,000 cases of melioidosis are estimated to occur each year; 85,000 (52%) of these patients die. Pneumonia is present in over 50% of melioidosis cases and more than doubles the risk of death. Yet, to develop novel, targeted therapeutics necessitates a deeper understanding of pulmonary and systemic mechanisms of host defense. Our team combines expertise in human and experimental melioidosis, pulmonary host defense, sepsis, and bioinformatics. We have developed a robust murine model of Bps pneumonia displaying mild and severe disease phenotypes. In parallel we have performed unbiased multi-omics analyses on a large prospective cohort of hospitalized patients with infection in NE Thailand with the goal of classifying melioidosis cases and understanding the host response to Bps. We identified distinct transcriptional and metabolomic profiles associated with melioidosis compared to other infected patients, and have built robust classifiers in each omics domain to predict death in human melioidosis. However, to comprehensively investigate mechanistic underpinnings requires a tractable experimental model with sufficient comparability to human disease. Moreover, to study the lethality of respiratory melioidosis requires sampling of lung tissue. We hypothesize that applying a comparative multi-omic approach to mice and humans with respiratory melioidosis will both a) yield critical insights into the pulmonary host defense mechanisms that fail to contain the infection and contribute to severe outcomes and b) establish comparability of the experimental murine model with human infection. We submit the following specific aims: 1). Define the temporal trajectory of multi-omic features of systemic host defense in murine respiratory melioidosis and identify perturbations representing success or failure of host defense. 2) Define lung cell-specific transcriptomic changes in murine respiratory melioidosis and identify signals that are associated with success or failure of pulmonary host defense. 3) Identify shared multi-omic signatures between murine and human respiratory melioidosis. The results of these studies will generate a rich compendium of data about the systemic and pulmonary host response to murine respiratory melioidosis and provide novel and comprehensive insights into the heterogeneity and key biological pathways underlying failed host response phenotypes of melioidosis pneumonia. Intersecting these findings with existing human melioidosis data will help to define clinically relevant targets for further investigation while simultaneously providing essential information about advantages and limitations of the animal model in recapitulating human infection at the multi-omic level.

项目概要 类鼻疽是一种通常致命的感染，由吸入、接种或摄入革兰氏阴性菌引起 兼性细胞内病原体和 1 级选择病原体拟鼻疽伯克霍尔德杆菌 (Bps)。最近，BPS 从美国南部的土壤中分离出来。全球有 165,000 例类鼻疽病例 估计每年都会发生；其中 85,000 名 (52%) 患者死亡。超过50%的人患有肺炎 类鼻疽病例和死亡风险增加一倍以上。然而，开发新颖的靶向疗法 需要更深入地了解宿主防御的肺部和全身机制。我们的团队 结合了人类和实验性类鼻疽、肺宿主防御、败血症和 生物信息学。我们开发了一种稳健的 Bps 肺炎小鼠模型，表现出轻度和重度 疾病表型。与此同时，我们对大型前瞻性研究进行了公正的多组学分析 泰国东北部住院感染患者队列，目的是对类鼻疽病例进行分类和 了解主机对 Bps 的响应。我们确定了不同的转录和代谢组学特征 与其他感染患者相比，与类鼻疽相关，并且在每个组学中建立了强大的分类器 预测人类类鼻疽死亡的域。但要全面考察其机理 基础需要一个易于处理的实验模型，与人类疾病具有足够的可比性。 此外，为了研究呼吸道类鼻疽的致死率，需要对肺组织进行取样。我们假设 对患有呼吸道类鼻疽病的小鼠和人类应用比较多组学方法将： 对肺部宿主防御机制的重要见解，该机制无法遏制感染并有助于 b) 建立实验鼠模型与人类感染的可比性。我们 提出以下具体目标： 1)．定义系统宿主多组学特征的时间轨迹 小鼠呼吸道类鼻疽的防御并识别代表宿主成功或失败的扰动 防御。 2) 定义小鼠呼吸道类鼻疽病中肺细胞特异性转录组变化并鉴定 与肺部宿主防御的成功或失败相关的信号。 3）识别共享的多组学 小鼠和人类呼吸道类鼻疽之间的特征。这些研究成果将产生丰富的 关于小鼠呼吸道类鼻疽的全身和肺部宿主反应的数据概要 为失败背后的异质性和关键生物学途径提供新颖而全面的见解 类鼻疽肺炎的宿主反应表型。将这些发现与现有的人类相交叉 类鼻疽数据将有助于确定临床相关目标以供进一步研究，同时 提供有关动物模型在再现人类方面的优点和局限性的基本信息 多组学水平的感染。