Multi-omics of murine respiratory melioidosis

项目总结 类鼻疽病是一种因吸入、接种或摄入革兰氏阴性菌而引起的致命感染。 兼性细胞内病原体和Tier 1选择剂假鼻疽伯克霍尔德氏菌(BPS)。BPS最近 从美国南部的土壤中分离出来。在世界范围内，165,000例类鼻疽病例是 估计每年发生；这些患者中有85,000人(52%)死亡。肺炎出现在超过50%的 类鼻疽病例和死亡风险增加一倍以上。然而，为了开发新的、有针对性的治疗方法 需要对宿主防御的肺和系统机制有更深入的了解。我们的团队 结合了人类和实验性类鼻疽病、肺宿主防御、败血症和 生物信息学。我们已经建立了一种显示轻度和重度的BPS肺炎小鼠模型。 疾病表型。与此同时，我们在一个大的前景下进行了无偏见的多组学分析 泰国东北部住院感染患者队列，目标是对类鼻疽病例和 了解主机对BPS的响应。我们鉴定了不同的转录和代谢组学特征 与其他感染患者相比，与类鼻疽病相关，并在每个组学中建立了强大的分类器 预测人类类鼻疽病死亡的领域。然而，要全面考察机械论 支撑需要一个易于处理的实验模型，与人类疾病有足够的可比性。 此外，要研究呼吸性类鼻疽病的致命性，需要对肺组织进行采样。我们假设 对患有呼吸性类鼻疽病的小鼠和人类应用比较多组学方法将产生： 对肺宿主防御机制的关键见解，这些机制未能控制感染并有助于 B)建立实验小鼠模型与人类感染的可比性。我们 提交以下具体目标：1)。确定系统寄主多组学特征的时间轨迹 小鼠呼吸性类鼻疽病的防御和识别代表宿主成败的扰动 防守。2)确定呼吸性类鼻疽病小鼠肺细胞特异性转录改变，并鉴定 与肺宿主防御成功或失败相关的信号。3)识别共享多体 小鼠和人类呼吸道类鼻疽病之间的特征。这些研究的结果将产生丰富的 小鼠呼吸性类鼻炎的系统和肺宿主反应数据概要 对故障背后的异质性和关键生物途径提供新的、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 类鼻疽病的数据将有助于确定临床相关的目标，以便进行进一步的研究，同时 提供有关动物模型在重述人类方面的优点和局限性的基本信息 多基因组水平的感染。

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.