Mechanisms by Which Alcohol-Induced Dysbiosis Impairs Host Defense Against Klebsiella Pneumoniae

酒精引起的生态失调损害宿主对肺炎克雷伯氏菌的防御的机制

• 批准号: 10022082
• 负责人: Derrick R Samuelson
• 金额: $ 24.79万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022082
• 关键词: Accounting; Adoptive Transfer; Alcohol consumption; Alcohols; Animals; Bacterial Infections; Bacterial Pneumonia; Biological Models; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Cessation of life; Clinical Research; Data; Disease; Environment; Ethanol; Functional disorder; Germ-Free; Growth and Development function; Host Defense; Immune; Immune response; Immunologics; Impairment; Infection; Intestinal permeability; Intestines; Investigation; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Link; Location; Lung; Lung infections; Mediating; Metabolic; Morbidity - disease rate; Mus; Mycoses; Patients; Phase; Play; Pneumonia; Predisposition; Publishing; Research; Research Infrastructure; Research Proposals; Respiratory Tract Infections; Risk Factors; Role; Scientist; T cell therapy; T-Lymphocyte; Testing; Virulent; Virus Diseases; alcohol effect; alcohol use disorder; disability; dysbiosis; experience; experimental study; global health; gut microbiota; gut-lung axis; immunoregulation; inflammatory disease of the intestine; metabolomics; microbial; microbial community; microbiota; mortality; mouse model; novel; pathogen; pathogenic bacteria; preclinical study; premature; programs; respiratory; trafficking

Project Summary/Abstract: Alcohol use disorders (AUD) are a significant global health burden. AUDs are an established risk factor for bacterial pneumonia, which accounts for ~3.1 million deaths annually. AUD patients are more frequently infected with highly virulent respiratory pathogens and experience increased morbidity and mortality from these infections, with Klebsiella pneumoniae being overrepresented in patients with AUDs. Mortality from Klebsiella pneumonia in patients with AUDs is double that from other pathogens. Further, preclinical and clinical studies show that alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis), yet no published data exist linking alcohol-mediated intestinal dysbiosis with respiratory host defense dysfunction and no attempt has been made to isolate the direct effects of alcohol from those resulting from intestinal dysbiosis. We have developed a mouse model system that enables us to investigate the immune modulatory effects of alcohol-associated dysbiosis and isolate the host responses to K. pneumoniae mediated directly or indirectly by ethanol-associated dysbiosis. Preliminary studies using fecal transfer show that alcohol-naïve animals recolonized with microbiota isolated from alcohol-fed mice have increased susceptibility to K. pneumoniae compared to mice recolonized with a control microbiota. The overall hypothesis to be tested in the proposed study is that alcohol-mediated dysbiosis increases intestinal inflammation and permeability, which leads to intestinal sequestration of T-cells, altered lung specific T-cell trafficking, and increased susceptibility to Klebsiella pneumoniae. I will test my hypothesis using both a metabolomics and immunological approach. Aim 1 will test the prediction that alcohol-dysbiosis promotes intestinal inflammation and permeability. I will utilize fecal adoptive transfer and cell culture experiments to determine the microbial and metabolic constituents that promote intestinal inflammation and permeability. Aim 2 will examine the impact of alcohol-dysbiosis on intestinal T-cell programing and sequestration. I will use T-cell adoptive transfer experiments to determine the effects of alcohol-dysbiosis on the location/sequestration of T-cells prior to respiratory infection. Aim 3 will test the prediction that alcohol-dysbiosis impairs lung specific T-cell trafficking. I will assess T-cell trafficking using microbial and metabolite primed T-cells adoptively transferred into alcohol-naïve animals recolonized with an alcohol-dysbiotic or pair-fed microbiota. The proposed studies will use a novel model system to clarify the role of the microbiota in host immune responses, particularly with regard to AUDs and respiratory infection. The results from these studies will provide data to support an R01 submission focused on the immunomodulatory effects of alcohol-induced dysbiosis on the gut-lung axis. The scientific environment, and the research infrastructure provided by the UNMC will be instrumental in my growth and development as an independent scientist.

项目摘要/摘要：酒精使用障碍（AUD）是重要的全球健康伯恩。澳元是一个 细菌性肺炎的确定危险因素，每年约为310万人死亡。 aud患者 经常感染高毒性呼吸道病原体，并且经历增加了发病率和 这些感染的死亡率，肺炎的克雷伯氏菌患者代表过多。 AUDS患者的克雷伯菌肺炎的死亡率是其他病原体的两倍。更远， 临床前和临床研究表明，酒精消耗伴随着正常的肠道微生物 社区（营养不良），但没有公开的数据，将酒精介导的肠道营养不良与呼吸道联系起来 宿主的防御功能障碍，并且没有试图将酒精的直接影响与那些人隔离 由肠道营养不良导致。我们已经开发了一个鼠标模型系统，使我们能够研究 酒精相关性营养不良的免疫调节作用和隔离宿主对肺炎链球菌的反应 直接或间接地通过与乙醇相关的营养不良介导。使用粪便转移的初步研究表明 从酒精喂养小鼠中分离出的菌群识别的酒精含量提高了敏感性 与用对照微生物群识别的小鼠相比，肺炎。要测试的总体假设 在拟议的研究中，酒精介导的营养不良增加了肠道注射和渗透性， 这导致了T细胞的肠道，改变了肺特异性T细胞运输并增加了 对克雷伯氏菌肺炎的敏感性。我将使用代谢组学和免疫学检验我的假设 方法。 AIM 1将测试酒精育促进性促进肠道注射和渗透性的预测。 我将利用粪便自适应转移和细胞培养实验来确定微生物和代谢 促进肠道注射和渗透性的成分。 AIM 2将检查酒精饮食的影响 在肠道T细胞编程和隔离上。我将使用T细胞自适应转移实验 确定酒精 - 杂交对呼吸道感染之前T细胞位置/隔离的影响。 AIM 3将测试酒精育伴侣型会损害肺特异性T细胞运输的预测。我将评估T细胞 使用微生物和代谢产物的T-T细胞自适应地转移到饮酒的动物中的运输 用酒精饮食或成对喂养的微生物群识别。 拟议的研究将使用新型模型系统来阐明菌群在宿主免疫中的作用 反应，特别是在aud和呼吸道感染方面。这些研究的结果将提供 支持R01提交的数据，重点是酒精诱导的营养不良的免疫调节作用对 肠肺轴。 UNMC提供的科学环境以及提供的研究基础设施 作为我作为独立科学家的成长和发展的作用。