Enhancing the I AM GOLD study with single-cell deep phenotyping and machine learning meta-analysis

项目概要/摘要 HIV 感染者患慢性阻塞性肺疾病 (COPD) 的风险增加，这是第三大主要疾病 全世界的死亡原因。在本提案中，我们的长期目标是确定潜在的机制 感染艾滋病毒后患慢性阻塞性肺病的风险增加。我们的中心假设是 Th17 增强驱动炎症 和以伽马变形菌为主的慢性气道微生物群相互作用，导致肺阻塞 HIV个体中的疾病。该假设基于以下证据。首先，我们在艾滋病毒中发现—— 未感染的 COPD 患者认为 Th17 驱动的气道炎症的基因组特征标志着 COPD 患有功能性小气道疾病的亚组，被认为先于肺气肿。二、Th17驱动 炎症是一种传统上被认为可以防御细菌的途径，但在 HIV 呼吸道中会增强 患者。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，有 肺功能下降的风险较高，有一些亚组具有明显的下呼吸道微生物特征 具有不同免疫反应的社区。一个亚组的气道以假单胞菌科为主 微生物群和炎症基因表达。伽马变形菌，包括假单胞菌，是 常见于 COPD，并且与 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可能在以下地区面临更高的慢性病风险 持续的菌群失调和低水平的 Th17 驱动的慢性炎症。我们提出的具体目标 将使用我们的艾滋病毒相关国际多中心研究中现有的和新收集的样本 COPD、I AM OLD（炎症、衰老、微生物和阻塞性肺病），其中艾滋病毒参与者 乌干达和旧金山在急性肺炎发生时入组并进行纵向随访。目标1将 识别急性发作时的气道微生物群落和炎症基因表达标记物 感染与随后发生的慢性阻塞性肺病和艾滋病毒肺功能下降有关。目标2将 识别慢性稳定期间的气道微生物群落和炎症基因表达标记物 与没有慢性阻塞性肺病（HIV COPD-）的参与者相比，艾滋病毒慢性阻塞性肺病患者的疾病加重。在目标 3 中，我们 将进行气道微生物组、微生物和人类转录组、代谢组的综合分析 HIV COPD 的肺部影像学变化。我们预计会出现以下结果： 1) 识别 在两个国际国家中，与 HIV COPD 相关的主要气道微生物组-宿主反应相互作用 风险人群，2) 鉴定与特定微生物群落相关的代谢组改变，以及 HIV COPD 中的炎症反应，3) 相关放射学异常范围的描述 HIV COPD 中微生物组与宿主反应的相互作用。我们期望这些成果能够产生积极的影响 影响，提供了对艾滋病毒感染者中慢性阻塞性肺病风险增加的生物学基础的新认识 可以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.