Dysbiosis Impact on Lung Disease in HIV (DImpL) Study

HIV 中生态失调对肺部疾病的影响 (DImpL) 研究

• 批准号: 9977793
• 负责人: Barbara Methe
• 金额: $ 46.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977793
• 关键词: Affect; Age; Anti-Inflammatory Agents; Antioxidants; Automobile Driving; Bacteria; Bioenergetics; Bronchoalveolar Lavage; Cell Separation; Cells; Chronic Obstructive Airway Disease; Coculture Techniques; Data; Development; Disease; Epithelial Cells; Event; Fc Receptor; Gene Expression; Genes; Genetic Transcription; HIV; Health; Homeostasis; Human; Human immunodeficiency virus test; IL6 gene; Immune; Immune response; Immune system; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Deficiency Syndromes; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Investigation; Knowledge; Lead; Longitudinal Studies; Lung; Lung Inflammation; Lung diseases; Maps; Metabolic; Methods; Microbe; Modality; Modeling; Morbidity - disease rate; Outpatients; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Play; Population; Pulmonary Emphysema; Research; Resources; Respiratory Signs and Symptoms; Respiratory physiology; Resveratrol; Role; SIV; Shapes; Smoking; Structure; Surveys; Taxonomy; Techniques; Test Result; Testing; Therapeutic Agents; Validation; Work; airway obstruction; antiretroviral therapy; bacterial community; bacterial metabolism; cohort; dysbiosis; extracellular; fecal microbiota; functional disability; gut microbiome; gut microbiota; improved; lung injury; lung microbiome; lung microbiota; member; metabolome; metabolomics; metatranscriptome; metatranscriptomics; microbial; microbial community; microbial host; microbiome; microorganism interaction; mortality; nonhuman primate; novel; novel marker; novel therapeutics; prevent; programs; stool sample; transcriptomics

ABSTRACT Chronic obstructive pulmonary disease (COPD), which encompasses airway obstruction and/or emphysema, is a growing cause of morbidity and mortality in HIV+ individuals in the current era. Pathogenesis of HIV- associated COPD is poorly understood, but shifts in the lung or gut microbiome may play a role. Studies of the lung microbiome have focused primarily on taxonomic characterization of bacterial communities; however, these taxonomic analyses do not capture functional differences in the microbial communities, focus solely on bacteria, and do not identify specific microbes that stimulate the host immune system, thus potentially missing key distinguishing features critical for disease pathogenesis. Our preliminary data demonstrate important differences in inflammation, host and microbial gene expression, and the metabolome in HIV COPD, suggesting a functional impact of the lung microbiome. The role of the gut microbiome, which can shape immune events in the lung, has also not been investigated in HIV COPD, but given the dysbiosis found in the gut in HIV and relationship of the gut microbiome to inflammation, it may also play a role in HIV COPD. Our overall hypothesis is that functional dysbiosis in HIV+ individuals alters host homeostasis contributing to COPD. Our primary aims are: (1) To characterize associations between functional profiles of microbes and host in the lung in HIV and COPD. We will utilize our ongoing Lung HIV Research Cohort to examine lung microbial and transcriptomic signatures that identify COPD in HIV and test specific causal pathways identified in a validation cohort. We will also analyze stool samples to determine relationship of the gut microbial community to lung function and inflammation in HIV. (2) To test the hypothesis that bacteria recognized by the host differ in HIV+ individuals with COPD compared to those with normal lung function and that these bacteria provoke a heightened inflammatory response. As taxonomic surveys do not differentiate bacteria that are provoking an immune response from those that are merely innocent bystanders, we will then employ cell- sorting of immunoglobulin (Ig)-bound lung bacteria as a novel method to identify members of the bacterial community recognized by the host. We will investigate the effects of these bacteria on lung cell gene expression and inflammation as well as the ability of therapeutic agents such as anti-IL6 receptor antibodies to block bacterial-induced inflammation. (3) To examine longitudinal changes in the lung and gut microbiome in a non-human primate model of HIV and COPD. Studies of COPD are also limited by investigation after development of disease, and we will utilize a non-human primate model to perform a longitudinal study of the impact of lung and gut microbiota on COPD development. These studies will improve our understanding of HIV-associated COPD and will test novel treatment modalities. This project will leverage existing resources to fill gaps in knowledge about the role of the microbiome in HIV-associated COPD, identify novel biomarkers of lung disease, and test new therapeutics.

抽象的 包括气道阻塞和/或肺气肿的慢性阻塞性肺疾病（COPD）是 在当前时代，艾滋病毒+个体发病率和死亡率的日益增长的原因。 HIV的发病机理 相关的COPD知之甚少，但是肺或肠道微生物组的变化可能起作用。研究 肺微生物组主要集中于细菌群落的分类表征。然而， 这些分类学分析不会捕获微生物群落的功能差异，而仅关注 细菌，并且不鉴定刺激宿主免疫系统的特定微生物，因此可能缺失 关键区别特征对于疾病发病机理至关重要。我们的初步数据表明很重要 炎症，宿主和微生物基因表达和HIV COPD中的代谢组的差异， 提示肺微生物组的功能影响。肠道微生物组的作用，可以塑造 肺中的免疫事件也没有在HIV COPD中进行调查，但鉴于在 HIV中的肠道以及肠道微生物组与炎症的关系，它也可能在HIV COPD中发挥作用。我们的 总体假设是，HIV+个体中的功能性营养不良改变了宿主的稳态促进 到COPD。我们的主要目的是：（1）表征微生物功能曲线和 霍夫和COPD的肺部宿主。我们将利用我们正在进行的肺HIV研究队列检查肺 微生物和转录组特征，鉴定在HIV中识别COPD并测试确定的特定因果途径 在验证队列中。我们还将分析粪便样品以确定肠道微生物的关系 社区肺功能和艾滋病毒炎症。 （2）检验以下假设： 与肺部功能正常的宿主相比，HIV+个体的COPD患者不同，这些细菌 引起炎症反应的增强。由于分类学调查没有区分 从仅是无辜旁观者的人产生免疫反应，我们将采用细胞 - 免疫球蛋白（IG）结合肺细菌的分选作为一种新方法，可鉴定细菌的成员 社区被主持人认可。我们将研究这些细菌对肺部细胞基因的影响 表达和炎症以及治疗剂（例如抗IL6受体抗体）的能力 阻断细菌引起的炎症。 （3）检查A中肺和肠道微生物组的纵向变化 艾滋病毒和COPD的非人类灵长类动物模型。 COPD的研究也受到调查的限制 疾病的发展，我们将利用非人类灵长类动物模型对 肺和肠道微生物群对COPD发育的影响。这些研究将提高我们对 与HIV相关的COPD，将测试新型治疗方式。该项目将利用现有资源来 填补有关微生物组在与HIV相关的COPD中的作用的知识的空白，识别新型生物标志物 肺部疾病，并测试新的治疗剂。