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: 9383358
• 负责人: Barbara Methe
• 金额: $ 49.94万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383358
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Automobile Driving; Bacteria; Bioenergetics; Bronchoalveolar Lavage; Cell Separation; Cells; Chronic Obstructive Airway Disease; Coculture Techniques; Communities; Data; Development; Disease; Epithelial Cells; Event; Fc Receptor; Feces; 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; Oxidative Stress; Pathogenesis; Pathway interactions; Play; Population; Pulmonary Emphysema; Research; Resources; Respiratory Signs and Symptoms; Respiratory physiology; Resveratrol; Role; SIV; Sampling; Shapes; Smoking; Structure; Surveys; Taxonomy; Techniques; Test Result; Testing; Therapeutic Agents; Validation; Work; airway obstruction; antiretroviral therapy; bacterial metabolism; cohort; extracellular; functional disability; gut microbiome; gut microbiota; improved; lung injury; member; metabolome; metabolomics; microbial; microbial community; microbial host; microbiome; microbiota; microorganism interaction; mortality; nonhuman primate; novel; novel marker; novel therapeutics; prevent; programs; 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 慢性阻塞性肺疾病（COPD），包括气道阻塞和/或肺气肿，是 当今时代，艾滋病病毒感染者的发病率和死亡率日益上升。 HIV的发病机制- 相关的慢性阻塞性肺病尚不清楚，但肺部或肠道微生物组的变化可能发挥了作用。研究的 肺微生物组主要关注细菌群落的分类学特征；然而， 这些分类学分析并未捕获微生物群落的功能差异，仅关注 细菌，并且不识别刺激宿主免疫系统的特定微生物，因此可能会丢失 对疾病发病机制至关重要的关键区别特征。我们的初步数据表明重要 HIV COPD 中炎症、宿主和微生物基因表达以及代谢组的差异， 表明肺微生物组的功能影响。肠道微生物组的作用，可以塑造 肺部的免疫事件，也没有在艾滋病毒慢性阻塞性肺病中进行研究，但考虑到在肺部发现的菌群失调 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 慢性阻塞性肺病中发挥作用。我们的 总体假设是，HIV+个体的功能失调改变了宿主体内平衡，从而促进 慢性阻塞性肺病。我们的主要目标是：（1）表征微生物功能谱与 HIV 和 COPD 的肺部宿主。我们将利用我们正在进行的肺部艾滋病毒研究队列来检查肺部 微生物和转录组学特征可识别 HIV 中的慢性阻塞性肺病并测试已确定的特定因果途径 在验证队列中。我们还将分析粪便样本以确定肠道微生物之间的关系 HIV 肺功能和炎症的社区。 (2) 检验细菌被识别的假设 与肺功能正常的人相比，患有 COPD 的 HIV+ 个体的宿主有所不同，并且这些细菌 引起炎症反应加剧。由于分类学调查无法区分细菌 激发那些无辜旁观者的免疫反应，然后我们将使用细胞- 对免疫球蛋白 (Ig) 结合的肺部细菌进行分选作为识别细菌成员的新方法 主办方认可的社区。我们将研究这些细菌对肺细胞基因的影响 表达和炎症以及治疗剂（例如抗 IL6 受体抗体）的能力 阻止细菌引起的炎症。 (3) 检查肺和肠道微生物组的纵向变化 HIV和COPD的非人类灵长类动物模型。 COPD 的研究也受到以下调查的限制： 疾病的发展，我们将利用非人类灵长类动物模型来进行纵向研究 肺和肠道微生物群对慢性阻塞性肺病（COPD）发展的影响。这些研究将增进我们对 与艾滋病毒相关的慢性阻塞性肺病，并将测试新的治疗方式。该项目将利用现有资源 填补关于微生物组在艾滋病毒相关慢性阻塞性肺病中的作用的知识空白，确定新的生物标志物 肺部疾病，并测试新疗法。