Pathogenesis of Obstruction/Emphysema and the Microbiome (POEM) in HIV

描述(由申请人提供)：艾滋病毒携带者的微生物区系可能在各种疾病中发挥重要作用，但艾滋病毒携带者肺部微生物群的性质尚未被研究。高通量的DNA测序技术现在可以检查复杂的微生物群落，包括无法培养的生物体。这些技术有可能提供有关艾滋病毒及其相关肺部疾病期间肺部事件的重要信息。慢性阻塞性肺疾病(COPD)在当前艾滋病毒感染的时代特别令人关注。HIV相关性COPD的发病机制尚不清楚，但一种或多种感染可上调HIV在肺部的表达，放大肺部炎症反应，并导致蛋白水解酶或促凋亡因子的释放。我们小组的数据表明，在HIV-F受试者中，肺孢子虫的低水平感染增加，并与解剖性肺气肿相关。其他感染单独或合并可能在疾病发病机制中起重要作用。元基因组学技术的应用将使我们能够确定微生物种群的模式和变化，这些微生物在肺气肿的发病和发展中发挥关键作用。这项建议的总体目标是确定HIV-I和HIV受试者中的呼吸道微生物区系(或微生物区系)，并利用我们正在进行的队列确定其在HIV相关COPD的发病和进展中的作用。该提案的具体目的是：1.比较HIV感染者和非HIV感染者呼吸道微生物群落结构。2.验证人类免疫缺陷病毒感染者与非慢性阻塞性肺病患者的呼吸道微生物区系不同，并与COPD进展有关的假设。3.验证血液中的细菌产物在患有慢性阻塞性肺疾病的HIV-f受试者中可检测到并与免疫激活有关的假设。我们将对HIV和HIV-I受试者进行口腔冲洗、诱导痰、支气管镜检查和抽血，并进行高通量病毒元基因组学以及细菌、真菌和原虫16S rDNA分析，以表征微生物群的多样性。结果将用于确定存在哪些微生物，它们的相对比例，它们的位置，以及它们与艾滋病毒和慢性阻塞性肺病的关系。相关性(见说明)：这项建议将帮助我们确定艾滋病毒感染者的肺部存在哪些感染，以及这些感染如何解释为什么艾滋病毒感染者比未感染艾滋病毒的人更快发展为肺气肿。这些信息将帮助我们了解和治疗这些患者以及许多患有肺气肿的非艾滋病毒感染者的肺气肿。

DESCRIPTION (provided by applicant): Microbial flora in persons with HIV likely play an important role in various diseases, but the nature of the microbiome in the lungs of persons with HIV has not been studied. High-throughput, DNA sequencing technologies now allow examination of complex microbial communities including organisms that cannot be cultured. These techniques have potential to yield important information about events in the lung during HIV and its associated pulmonary disorders. Chronic obstructive pulmonary disease (COPD) is of particular interest in the current era of HIV infection. Pathogenesis of HIV-associated COPD is poorly understood, but one or more infections may upregulate expression of HIV in the lungs, amplify the pulmonary inflammatory response, and lead to release of proteases or pro-apoptotic factors. Data from our group suggest that low level infection with Pneumocystis is increased in HIV-F subjects and associated with anatomic emphysema. Other infections alone or in combination are likely to be important in disease pathogenesis. Application of metagenomic techniques will allow us to determine patterns and changes in the population of microbes that play a key role in the pathogenesis and progression of emphysema in this population. The overall goals of this proposal are to determine the respiratory microbial flora (or microbiota) in HIV-I- and HIV- subjects and to establish its role in pathogenesis and progression of HIV-associated COPD using our ongoing cohorts. Specific aims of the proposal are: 1. To compare the microbial community structure in the respiratory tract in subjects with and without HIV infection. 2. To test the hypothesis that the respiratory microbiome in HIV-I- subjects with COPD differs from that in HIV-f subjects without COPD and is related to COPD progression. 3. To test the hypothesis that bacterial products in the blood are detectable in HIV-f subjects with COPD and are associated with immune activation. We will perform oral wash, sputum induction, bronchoscopy, and blood draws in HIV- and HIV-I- subjects and carry out high-throughput virus metagenomics and bacterial, fungal and protozoal 16S rDNA analyses for characterization of microbiome population diversity. Results will be used to determine which microbes are present, their relative proportions, their location, and their relationship to HIV and COPD. RELEVANCE (See instructions): This proposal will help us determine which infections are present In the lungs of people with HIV and how the infections might explain why HIV-infected individuals develop emphysema faster than non-HIV-infected people. This information will help us understand and treat emphysema in these patients and in the many non-HIV-infected people who suffer from emphysema.