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，但即使在有效治疗的患者中，感染性和非感染性呼吸道疾病仍然是主要问题。此外，慢性肺部疾病现在变得越来越重要，包括加速的COPD。虽然免疫功能障碍显然在肺部感染中起着核心作用，但病原体的出现是由微生物群内相互作用和宿主免疫系统相互作用的微生物之间的复杂关系引起的。此外，虽然下呼吸道通常是无菌的，但许多条件，如吸烟，COPD和慢性疾病，使定植，这有助于肺部炎症和损伤。尽管免疫缺陷、肺部感染和慢性肺部疾病重叠，但对HIV/AIDS中呼吸道微生物组的变化、其与感染性并发症的关系以及在慢性肺部疾病中的作用知之甚少。分子技术的最新进展使分析复杂微生物种群的能力前所未有，揭示了通常不可培养或以前未鉴定的生物体的广泛社区。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，进行了为数不多的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体微生物组尚未研究，也不知道吸烟与艾滋病毒感染相结合时，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导致呼吸道微生物组的进行性变化。这些变化将受到ART诱导的免疫重建的调节：在HIV感染中，呼吸道微生物的改变有助于慢性炎症和加速COPD的发展;吸烟和饮食改变了微生物组。为了解决这些假设，我们将采用高密度深度测序来：（1）确定HIV感染和未感染个体的下呼吸道和上呼吸道微生物组;（2）确定进行性免疫缺陷和ART诱导的免疫重建的影响;（3）确定HIV感染和未感染COPD个体的呼吸道微生物组;（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）开发新方法来识别使用16 S测序无法识别的新型微生物组成分;（6）与其他HIV/肺部微生物组中心建立合作项目。相关性（参见说明）：人体与栖息在表面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，因此正常平衡可能会改变，但尚未对此进行研究。我们将研究呼吸系统的微生物如何在HIV感染中发生改变，以及这如何导致肺部并发症，这些并发症仍然是HIV/AIDS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.