Determining the Injury-Associated Microbial Nutrients that Facilitate Secondary Bacterial Infection in Acutely Injured Lungs

确定促进急性损伤肺部继发细菌感染的损伤相关微生物营养素

• 批准号: 10382601
• 负责人: Jennifer Marie Baker
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382601
• 关键词: Acute Lung Injury; Air; Award; Bacteria; Bacterial Infections; Bacterial Pneumonia; Bioinformatics; Biological Assay; Blood; Blood-Air Barrier; Bronchoalveolar Lavage Fluid; Carbohydrates; Cessation of life; Clinical; Coculture Techniques; Communication; Complement; Complication; Critical Illness; Data; Development; Edema; Environment; Etiology; Frequencies; Gene Expression; Gene Expression Profiling; Genes; Glucose; Goals; Growth; Health; Immune; Immunologics; Impairment; In Vitro; Injury; Intervention; Iron; Knock-out; Knowledge; Leadership; Liquid substance; Lung; Lung infections; Mass Fragmentography; Metabolic Pathway; Microbiology; Modeling; Morbidity - disease rate; Mus; Nutrient; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pneumonia; Proteins; Pseudomonas aeruginosa; Recovery; Research; Research Personnel; Research Training; Respiratory Tract Infections; Risk; Saline; Secondary to; Serum; Shapes; Staphylococcus aureus; System; Testing; Tissue-Specific Gene Expression; bacterial community; bacterial fitness; clinical development; dysbiosis; experimental study; fitness; host microbiome; improved; injured; lung injury; metabolomics; microbial; mortality; mouse model; mutant; novel; novel strategies; pathogen; pathogenic bacteria; predict clinical outcome; prevent; respiratory; skills; targeted treatment; training opportunity; transcriptome sequencing; uptake

PROJECT SUMMARY Secondary pneumonia occurs frequently in patients with acutely injured lungs and increases the mortality of acute lung injury. Although acute lung injury is caused by a variety of pulmonary and systemic insults, all etiologies of acute lung injury result in compromised integrity of the blood-air barrier, allowing an influx of protein- rich, serum-derived fluid in the pulmonary airspace. Consequently, the microenvironment within acutely injured lungs is radically altered from health and provides a selective advantage to the outgrowth of pneumonia- associated pathogens. However, the factors that enable bacterial growth in acutely injured lungs are unknown. The objective of this study is to determine which soluble factors in the injured lung enhance the survival of pneumonia-associated bacteria by serving as bacterial nutrients. Using the proposed research plan, we will test the central hypothesis that the influx of serum-derived edema into the injured lung microenvironment increases the diversity and quantity of substrates which can be taken up and metabolized by pneumonia- associated bacteria, enhancing bacterial growth and fitness in the injured lung microenvironment. We will test this hypothesis through the following specific aims: (1) determine the bacterial nutrient uptake systems and metabolic pathways that provide fitness advantages for pneumonia-associated bacteria in the injured lung microenvironment, and (2) determine the diversity and quantity of bacterial nutrient substrates that become available in the injured lung microenvironment and enhance bacterial growth. To accomplish these specific aims, we will employ Pseudomonas aeruginosa and Staphylococcus aureus, two of the most common pneumonia- associated pathogens, along with a murine model of oxygen-induced lung injury and a novel ex vivo culture system to compare differences in bacterial growth and gene expression between healthy and injured lung microenvironments. To complement the murine modeling and ex vivo bacterial culture, we will perform targeted metabolite analysis to detect the presence of host-derived nutrients that support bacterial growth in injured lungs. We will use bacterial knockouts, competitive co-culture, and in vitro nutrient modulation experiments to validate our findings. This study will identify specific, injury-associated nutrients that directly promote bacterial growth in acutely injured lungs and establish the influence of nutrient availability on the progression from respiratory dysbiosis to secondary bacterial infection in the context of acute lung injury. Furthermore, the results of this study will provide a mechanistic basis for the development of clinical interventions for patients with acute lung injury at risk for pneumonia. Successful completion of the proposed research and training plan will enable Ms. Baker to develop professional skills pertaining to communication and leadership and unique interdisciplinary expertise in pulmonary pathobiology, bacterial pathogenesis, and bioinformatics. This F31 award will be essential for her continued professional and scientific development and will equip her for the next step of her professional journey to become an independent academic researcher in the field of pulmonary host-microbiome interactions.

项目摘要 继发性肺炎常发生在急性肺损伤的患者中， 急性肺损伤虽然急性肺损伤是由各种肺部和全身性损伤引起的，但所有 急性肺损伤的病因导致血-气屏障的完整性受损，允许蛋白质- 肺部空气中有丰富的血清衍生液体。因此，急性损伤的微环境 肺从健康状态发生了根本性的改变，并为肺炎的发展提供了选择性的优势- 相关病原体。然而，使细菌在急性损伤的肺中生长的因素尚不清楚。 本研究的目的是确定损伤肺中哪些可溶性因子能提高肺损伤患者的存活率。 肺炎相关的细菌作为细菌营养素。利用拟议的研究计划，我们将测试 中心假设是血清源性水肿流入损伤的肺微环境 增加了可被肺炎吸收和代谢的底物的多样性和数量， 相关的细菌，增强细菌的生长和健康在受伤的肺微环境。我们 本文将通过以下具体目标来检验这一假设：（1）确定细菌的营养吸收系统 和代谢途径，为受伤肺部的肺炎相关细菌提供适应性优势 微环境，和（2）确定细菌营养底物的多样性和数量，成为 可用于受伤的肺微环境并增强细菌生长。为了实现这些具体目标， 我们将使用铜绿假单胞菌和金黄色葡萄球菌，两种最常见的肺炎， 相关病原体，沿着小鼠氧诱导肺损伤模型和新的离体培养 比较健康和损伤肺之间细菌生长和基因表达差异的系统 微环境为了补充小鼠建模和离体细菌培养，我们将进行靶向的 代谢物分析，以检测支持受损肺部细菌生长的宿主来源的营养物质的存在。 我们将使用细菌敲除、竞争性共培养和体外营养调节实验来验证 我们的发现这项研究将确定具体的，与伤害相关的营养物质，直接促进细菌生长， 急性损伤的肺，并建立营养物质的可用性对呼吸道疾病进展的影响， 在急性肺损伤的情况下，微生态失调导致继发性细菌感染。此外，这项研究的结果 将为急性肺损伤患者的临床干预措施的发展提供机制基础， 肺炎的风险。成功完成拟议的研究和培训计划将使贝克女士能够 发展有关沟通和领导能力的专业技能和独特的跨学科专业知识， 肺病理生物学、细菌发病机理和生物信息学。这个F31奖对她来说至关重要 持续的专业和科学发展，并将为她的专业旅程的下一步做好准备 成为肺部宿主-微生物组相互作用领域的独立学术研究人员。