Integrated Analysis of Microbial and Genomic data in Obstructive Lung Disease (I AM GOLD) Study

项目摘要/摘要 艾滋病毒携带者患慢性阻塞性肺疾病(COPD)的风险增加，居第三位 全球范围内的死因。在这项建议中，我们的长期目标是确定 慢性阻塞性肺病合并艾滋病毒感染的风险增加。我们的中心假设是增强的Th17驱动了炎症 慢性伽马蛋白细菌主导的呼吸道微生物群相互作用促进阻塞性肺 艾滋病患者中的疾病。这一假设基于以下证据。首先，我们在艾滋病毒中发现了- 未感染的COPD患者，Th17驱动的呼吸道炎症的基因组特征标志着COPD 有功能性小气道疾病的亚群，被认为是肺气肿的先兆。第二，Th17驱动 炎症，一种经典的防御细菌的途径，在艾滋病毒的呼吸道中得到加强。 病人。第三，我们的小组表明，在乌干达患有肺炎的艾滋病毒患者中， 肺功能下降的风险较高，有一些亚组的特征是明显的下呼吸道微生物 具有不同免疫反应的社区。一个亚群的呼吸道以假单胞菌科为主 微生物区系和炎症基因的表达。变形革兰氏菌，包括假单胞菌， 常见于COPD，与Th17炎症一样，与肺气肿有关。因此， 以假单胞菌科为主的肺炎亚群在#年患慢性病的风险可能更高 持续的生物失调和低水平的Th17导致了慢性炎症。我们提出的具体目标 将使用我们现有的和新收集的来自我们的国际多中心艾滋病毒相关研究的样本 慢性阻塞性肺病，我是老年人(炎症、衰老、微生物和阻塞性肺病)，艾滋病毒参与者在 乌干达和旧金山在发生急性肺炎时登记在册，纵向上紧随其后。目标1将 急性发作时呼吸道微生物群落和炎症基因表达标志物的确定 感染与随后发生的COPD和HIV患者的肺功能下降有关。目标2将 慢性稳定期呼吸道微生物群落和炎症基因表达标志物的鉴定 与没有COPD的参与者(HIV COPD-)相比，HIV COPD患者的病情加重。在《目标3》中我们 将对呼吸道微生物组、微生物和人类转录组、代谢组进行综合分析 以及HIV COPD患者的肺部X线改变。我们预计会出现以下结果：1)确定 与HIV COPD相关的主要呼吸道微生物群-宿主反应相互作用在两个国际研究中心- 风险人群，2)确定与特定微生物群落相关的代谢组改变和 HIV COPD的炎症反应，3)相关放射学异常范围的描绘 在HIV COPD中与微生物组-宿主反应相互作用。我们预计这些结果将产生积极的影响 影响，提供了对艾滋病毒中COPD风险增加的生物学基础的新理解- 可指导治疗干预的感染人群。

Project Summary/Abstract Patients with HIV are at increased risk for chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. In this proposal, our long-term goal is to identify the mechanisms underlying the increased risk of COPD with HIV infection. Our central hypothesis is that enhanced Th17 driven inflammation and chronic Gammaproteobacteria-dominated airway microbiota interact to contribute to obstructive lung disease in HIV+ individuals. This hypothesis is based on the following evidence. First, we have found in HIV- uninfected COPD patients that a genomic signature of Th17 driven airway inflammation marks a COPD subgroup with functional small airway disease, which is thought to precede emphysema. Second, Th17 driven inflammation, a pathway classically thought to defend against bacteria, is enhanced in the airways of HIV+ patients. Third, our group has shown that amongst Ugandan HIV+ patients with pneumonia, a population at higher risk for lung function decline, there are subgroups characterized by distinct lower airway microbial communities with differing immune responses. One subgroup had Pseudomonadaceae-dominated airway microbiota and inflammatory gene expression. Gammaproteobacteria, which includes Pseudomonas, are commonly found in COPD and, as with Th17 inflammation, are associated with emphysema. Thus, the Pseudomonadaceae-dominant pneumonia subgroup may be at higher risk for developing chronic disease in the setting of continued dysbiosis and low level Th17 driven chronic inflammation. Our proposed specific aims will use existing and newly collected samples from our international multi-center study of HIV-associated COPD, I AM OLD (Inflammation, Aging, Microbes and Obstructive Lung Disease), in which HIV+ participants in Uganda and San Francisco are enrolled at the time of acute pneumonia and followed longitudinally. Aim 1 will identify the airway microbial communities and inflammatory gene expression markers at the time of acute infection that are associated with subsequent incident COPD and lung function decline in HIV. Aim 2 will identify the airway microbial communities and inflammatory gene expression markers during chronic stable disease that are enhanced in HIV+COPD compared to participants without COPD (HIV+COPD-). In Aim 3 we will perform integrative analyses of the airway microbiome, microbial and human transcriptome, metabolome and lung radiographic changes in HIV+COPD. We anticipate the following outcomes: 1) identification of the predominant airway microbiome-host response interactions associated with HIV+COPD in two international at- risk populations, 2) identification of metabolome alterations associated with specific microbial communities and inflammatory responses in HIV+COPD, 3) delineation of the range of radiographic abnormalities associated with microbiome-host response interactions in HIV+COPD. We expect these outcomes to have a positive impact, providing a new understanding of the biology underlying the enhanced risk for COPD amongst the HIV- infected population which could direct therapeutic interventions.