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

项目概要/摘要 艾滋病毒感染者患慢性阻塞性肺疾病（COPD）的风险增加，这是第三大疾病。 全球范围内的死因。在本提案中，我们的长期目标是确定 COPD合并HIV感染的风险增加。我们的中心假设是Th 17增强驱动的炎症 和慢性γ-蛋白菌为主的气道微生物群相互作用， 艾滋病+患者。这一假设基于以下证据。首先，我们在艾滋病毒中发现- 未感染COPD患者的Th 17驱动的气道炎症的基因组特征标志着COPD 功能性小气道疾病亚组，被认为是肺气肿的先兆。第二，Th 17驱动 炎症，一种传统上被认为是防御细菌的途径，在HIV+的气道中增强 患者第三，我们的研究小组表明，在乌干达艾滋病毒阳性肺炎患者中， 肺功能下降的风险更高，有亚组的特征是不同的下呼吸道微生物 不同免疫反应的群体。一个亚组的气道以假单胞菌为主 微生物群和炎症基因表达。γ-变形菌，包括假单胞菌， 常见于COPD，与Th 17炎症一样，与肺气肿相关。因此 假单胞菌属占优势的肺炎亚组可能在以下人群中发展为慢性疾病的风险更高： 持续的生态失调和低水平的Th 17驱动的慢性炎症。我们提出的具体目标 将使用现有的和新收集的样本，从我们的国际多中心研究艾滋病毒相关的 慢性阻塞性肺病，我老了（炎症，衰老，微生物和阻塞性肺病），其中HIV+参与者在 乌干达和弗朗西斯科在急性肺炎时入组，并进行纵向随访。目标1将 确定急性呼吸道感染时的气道微生物群落和炎症基因表达标志物， 感染与随后发生COPD和HIV中肺功能下降相关。目标2将 确定慢性稳定期气道微生物群落和炎症基因表达标志物， 与无COPD的参与者（HIV+COPD-）相比，HIV+COPD中的疾病增强。在目标3中， 将对气道微生物组、微生物和人类转录组、代谢组进行综合分析， 和HIV+COPD的肺部放射学改变。我们预期以下结果：1）识别 在两个国际性研究中， 风险人群，2）识别与特定微生物群落相关的代谢组学改变， HIV+COPD中的炎症反应，3）描绘与HIV + COPD相关的放射学异常范围 与HIV+COPD中的微生物组-宿主反应相互作用。我们希望这些结果能产生积极的影响， 影响，提供了一个新的生物学基础的认识，增加了COPD的风险之间的艾滋病毒- 感染人群可以直接进行治疗干预。

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.