Human Respiratory Tract Microbiome in Health, HIV Infection and HIV Lung Disease

描述(由申请人提供)： 肺部并发症是未经治疗的艾滋病毒/艾滋病患者发病和死亡的主要原因，但即使在接受有效治疗的患者中，传染性和非传染性呼吸道疾病仍然是主要问题。此外，慢性肺部疾病现在正变得越来越重要，包括慢性阻塞性肺病的加速发展。虽然免疫功能障碍显然在肺部感染中起着核心作用，但病原体的出现是生态位内微生物之间相互作用和宿主免疫系统相互作用的复杂关系的结果。此外，虽然下呼吸道通常是无菌的，但许多情况下，如吸烟、慢性阻塞性肺病和慢性病会导致定植，这会导致肺部炎症和损伤。尽管免疫缺陷、肺部感染和慢性肺部疾病有重叠之处，但对HIV/AIDS呼吸道微生物群的变化、与感染并发症的关系以及在慢性肺部疾病中的作用知之甚少。最近分子技术的进步带来了前所未有的能力来分析复杂的微生物种群，揭示了广泛的群落，往往是不可培养的或以前未识别的生物体。我们小组率先使用高密度焦磷酸测序，并在SIV/猕猴肠道模型中，开展了少数关于免疫缺陷病毒对微生物组影响的研究之一。艾滋病毒如何改变人类微生物群尚未得到研究，目前尚不清楚当吸烟与艾滋病毒感染合并时，对呼吸道微生物群的影响是否会导致艾滋病毒感染的肺部并发症或加速COPD。我们假设HIV导致呼吸道微生物群的渐进性变化。这些变化将通过ART诱导的免疫重建来调节：在HIV感染中，爱的呼吸道微生物区系的变化有助于慢性炎症和COPD的加速发展；微生物群受到Smokinase和饮食的修改。为了解决这些假设，我们将使用高密度深度测序来：(1)定义艾滋病毒感染者和非感染者的下呼吸道和上呼吸道微生物组；(2)确定渐进性免疫缺陷和ART诱导的免疫重建的影响；(3)定义艾滋病毒感染者和非感染者的呼吸道微生物组；(4)确定吸烟和饮食对呼吸道微生物组的影响以及呼吸道和肠道之间的关系；(5)开发新的方法来鉴定用16S测序无法鉴定的新的微生物组成分；(6)与其他艾滋病毒/肺微生物组中心建立合作项目。相关性(见说明)：人体与体表和体腔中的微生物保持平衡，人们越来越认识到这些微生物与宿主之间的关系有助于健康和疾病。免疫缺陷是艾滋病毒/艾滋病的核心组成部分，因此很可能会改变正常的平衡，但这一点还没有被研究过。我们将研究在HIV感染中呼吸系统的微生物是如何改变的，以及这如何导致肺部并发症，这些并发症仍然是艾滋病毒/艾滋病患者最严重的问题之一。

DESCRIPTION (provided by applicant): Pulmonary complications are a principal cause of morbidity and mortality in untreated HIV/AIDS, but infectious and noninfectious respiratory illnesses remain major problems even in effectively treated patients. In addition, chronic lung diseases are now emerging in importance, including accelerated COPD. While immune dysfunction clearly plays a central role in lung infections, the emergence of a pathogen results from complex relationships among microbial inhabitants within a niche that interact with each other and the host immune system. Also, while the lower respiratory tract is normally sterile, many conditions such as smoking, COPD and chronic illness enable colonization, which contribute to lung inflammation and injury. Despite the overlap of immune deficiency, pulmonary infections and chronic lung disease, little is knov/n about respiratory microbiome changes in HIV/AIDS, its relationship to infectious complications, and role in chronic pulmonary diseases. Recent advances in molecular technology have led to unprecedented ability to analyze complex microbial populations, revealing extensive communities of often unculturable or previously unidentified organisms. Our group pioneered the use of high density pyrosequencing and, in the SIV/macaque gut model, carried out one of the few studies of immunodeficiency virus effects on the microbiome. How HIV alters the human microbiome has not been examined, and it is unknown if effects on respiratory microbiota contribute to lung complications of HIV infection or accelerated COPD when smoking is combined with HIV infection. We hypothesize that HIV leads to progressive changes in the respiratory tract microbiome. and these changes will be modulated by ART-induced immune reconstitution: that alterations in lov^er respiratory tract microbiota contribute to chronic inflammation and accelerated development of COPD in HIV infection: and that the microbiome is modified by smokina and diet. To address these hypotheses we will employ high density deep sequencing to: (1) Define the lower and upper respiratory tract microbiome in HIV-infected and uninfected individuals; (2) Determine the effects of progressive immune deficiency and ART-induced immune reconstitution; (3) Define the respiratory microbiome in HIV-infected and uninfected individuals with COPD; (4) Determine the effects of smoking and diet on the respiratory microbiome, and relationship between respiratory tract and gut; (5) Develop new methods to identify novel microbiome constituents not identifiable using 16S sequencing; (6) Establish collaborative projects with other HIV/Lung Microbiome centers. RELEVANCE (See instructions): The human body lives in balance with microbes that inhabit surfaces and body cavities, and it is increasingly recognized that the relationship between these microbes and the host contribute to health and disease. Immune deficiency is a central component of HIV/AIDS so it is likely that the normal balance is altered, but this has not been studied. We will study how the microbes of the respiratory system are altered in HIV infection, and how this contributes to lung complications that remain among the most serious problems for people with HIV/AIDS.