Lung Microbiome and Pulmonary Inflammation/Immunity in HIV Infection

描述(由申请人提供)：人类免疫缺陷病毒(HIV)感染的肺间室以慢性炎症和严重的免疫紊乱为特征。虽然一些炎症变化可能是由于艾滋病毒在肺部的慢性刺激，但这些变化与肺病毒载量之间的相关性很差。因此，其他因素可能也在推动肺部的慢性炎症状态。鉴于这些患者已知的免疫缺陷，呼吸道定植新的或数量增加的感染病原体的可能性很高，而且很容易导致慢性炎症。因此，我们假设HIV感染者的肺炎症和免疫环境与宿主微生物群直接相关，而不是与肺部HIV负担有关，与未感染的人相比，免疫缺陷导致肺微生物群更加多样化，高效抗逆转录病毒治疗(HAART)使肺微生物群恢复正常。我们将利用现有的大量支气管肺泡灌洗样本，开始探索正常志愿者和艾滋病毒感染者的肺微生物群，并将其与局部肺部炎症的测量相关联。这些队列包括患有慢性阻塞性肺病的艾滋病毒感染者和那些在开始抗逆转录病毒治疗之前进行研究并纵向随访6-12个月的患者。我们还将前瞻性地研究从口咽到肺泡整个呼吸道的微生物群，以确定在上呼吸道发现的微生物群是否可以预测下呼吸道微生物群。为了实现我们的目标，我们提出了以下具体目标。(1)比较HIV感染者和正常志愿者的呼吸道微生物群；(2)直接关联HIV感染者和正常志愿者的呼吸道微生物群与肺部炎症环境的关系；(3)确定高效抗逆转录病毒治疗是否改变肺部微生物群和局部炎症反应；(4)比较HIV感染者和正常志愿者从口咽到肺泡的呼吸道微生物群。深入的分析将从16S和18S rRNA测序开始，以描绘存在于肺部的微生物的大致图景。将对可能识别的物种进行详细的超基因组鸟枪测序，以确定可能直接影响肺部免疫学和炎症环境的重要基因库。这些研究将极大地增强我们对健康和疾病中的肺环境的了解，并导致潜在的定义肺内稳态的新模型。相关性(见说明)：在这个项目中，我们将检查艾滋病毒感染者肺中存在的微生物菌群，以确定他们与非艾滋病毒感染者在所发现的微生物类型上是否存在差异。这些研究将增加我们对正常细菌如何定植我们的肺部如何影响健康和疾病的肺环境的理解。

DESCRIPTION (provided by applicant): The lung compartment in Human Immunodeficiency Virus (HIV) infection is characterized by chronic inflammation and severe immunologic derangements. While some of the inflammatory changes may be due to chronic stimulation by HIV in the lung, correlation between these changes and the lung viral load is poor. Thus other factors are likely driving the chronic inflammatory state in the lung. Given the known immunodeficiency in these patients, colonization of the respiratory tract with new or increased numbers of infectious pathogens is highly likely and easily could be contributing to chronic inflammation. Thus we hypothesize that the lung inflammatory and immunologic environment in HIV-infected subjects is directly related to the host microbiome rather than the pulmonary HIV burden, that the immunodeficiency seen leads to a more diverse pulmonary microbiome compared to uninfected subjects, and that highly active antiretroviral therapy (HAART) returns the pulmonary microbiome towards normal. We will make use of a large existing cohort of bronchoalvoelar lavage samples to begin exploring lung microbiomes in normal volunteers and HIV-infected subjects and correlate these with measures of local pulmonary inflammation. These cohorts include HIV-infected subjects with COPD and those studied prior to starting antiretroviral and followed longitudinally for 6-12 months. We will also prospectively study the microbiome along the entire respiratory tract from the oropharynx to the alveoli to determine if what is found in the upper tract can predict lower respiratory microbiomes. To accomplish our goals we propose the following Specific Aims. (1) To compare the respiratory microbiome between HIV-infected subjects and normal volunteers; (2) To directly correlate the relationship between the respiratory microbiome and the pulmonary inflammatory milieu in HIV-infected subjects and normal volunteers; (3) To determine if highly active antiretroviral therapy alters the pulmonary microbiome and local inflammatory response; and (4) To compare the respiratory microbiome in HIV-infected subjects and normal volunteers from the oropharynx to the alveoli. In depth analysis will start with 16s and 18s rRNA sequencing to paint a broad picture of the microorganisms present in the lung. Detailed metagenomic shotgun sequencing will be performed on prospectively identified species to characterize significant gene pools which may directly impact the pulmonary immunologic and inflammatory milieu These studies will greatly enhance our understanding of the lung environment in both health and disease and lead to potential new models defining pulmonary homeostasis. RELEVANCE (See instructions): In this project we will be examining the microbiological flora present in the lung of HIV-infected subjects to determine if there is a difference between them and non HIV-infected subject in the types of organisms found. These studies will add to our understanding of how normal bacteria colonizing our lungs influence the lung environment in health and disease.