Dysbiosis Impact on Lung Disease in HIV (DImpL) Study

摘要 慢性阻塞性肺疾病（COPD）包括气道阻塞和/或肺气肿， 在当今时代，这是艾滋病毒阳性个体发病率和死亡率不断上升的原因。艾滋病毒的发病机制- 相关的COPD知之甚少，但肺或肠道微生物组的变化可能起作用。的研究 肺微生物组主要集中于细菌群落的分类学表征;然而， 这些分类学分析并没有捕捉微生物群落中的功能差异，仅仅关注 细菌，并且不能识别刺激宿主免疫系统的特定微生物，因此可能缺失 对疾病发病机理至关重要的关键区别特征。我们的初步数据显示， 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，它可以塑造 肺中的免疫事件，也没有在HIV COPD中进行研究，但考虑到在肺中发现的生态失调， 肠道在HIV中的作用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 总体假设是，HIV+个体的功能性生态失调改变了宿主的稳态， COPD。我们的主要目的是：（1）表征微生物功能谱之间的关联， 艾滋病毒和慢性阻塞性肺病的肺部宿主。我们将利用我们正在进行的肺部HIV研究队列， 微生物和转录组学特征可识别HIV中的COPD，并检测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， 社区对肺功能和炎症的影响。(2)为了验证细菌识别的假设， 与肺功能正常的人相比，患有COPD的HIV+个体的宿主不同， 会引起更强烈的炎症反应由于分类学调查不能区分细菌， 激发那些仅仅是无辜旁观者的免疫反应，然后我们将使用细胞- 免疫球蛋白（IG）结合的肺细菌的分选作为鉴定细菌成员的新方法 被主持人认可。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如抗IL 6受体抗体 阻止细菌引起的炎症。(3)为了检查肺和肠道微生物组的纵向变化， HIV和COPD的非人灵长类动物模型。COPD的研究也受到研究的限制， 疾病的发展，我们将利用非人类灵长类动物模型进行纵向研究， 肺和肠道微生物群对COPD发展影响。这些研究将增进我们对 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， 填补了关于微生物组在HIV相关COPD中作用的知识空白， 肺部疾病，并测试新的疗法。

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.