Lung Microbiome and Pulmonary Inflammation/Immunity in HIV Infection

HIV 感染中的肺部微生物组和肺部炎症/免疫

• 批准号: 7936985
• 负责人: Homer L Twigg
• 金额: $ 75.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936985
• 关键词: Address; Affect; Alveolus; Anti-Retroviral Agents; Antibodies; Automobile Driving; Bacteria; Bronchoalveolar Lavage; CD4 Lymphocyte Count; Chronic; Chronic Obstructive Airway Disease; Disease; Environment; Gene Pool; Goals; HIV; Health; Highly Active Antiretroviral Therapy; Homeostasis; Immunity; Immunologic Deficiency Syndromes; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Instruction; Irrigation; Lead; Lung; Measures; Metagenomics; Modeling; Opportunistic Infections; Organism; Oropharyngeal; Paint; Participant; Patients; Phenotype; Pneumonia; Recording of previous events; Respiratory System; Respiratory tract structure; Ribosomal RNA; Sampling; Shotgun Sequencing; Smoking Status; Trees; Viral Load result; Virus Diseases; chemokine; cohort; cost; cytokine; microbiome; microorganism; pathogen; prospective; respiratory; volunteer

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.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染中的肺部室的特征是慢性炎症和严重的免疫危险。尽管某些炎症性变化可能是由于HIV在肺中的慢性刺激引起的，但这些变化与肺部病毒负荷之间的相关性很差。因此，其他因素可能正在推动肺部慢性炎症状态。考虑到这些患者的已知免疫缺陷，具有新的或增加的感染性病原体数量的呼吸道定植很可能会导致慢性炎症。因此，我们假设感染HIV受试者的肺炎症和免疫学环境与宿主的微生物组直接相关，而不是肺HIV负担，与未感染的受试者相比，所见的免疫缺陷会导致更多样化的肺微生物组，并且这种高度活跃的抗雷病毒治疗（Haart）伴随着pilloby sirobi siroby siroby siroby picky pillome collyary colly to pillonary picki s to pillonary pillome to pilly sick to pillonary s pollony s pollony。我们将利用大量现有的支气管腔灌洗样品来开始探索正常志愿者和受HIV感染受试者的肺微生物组，并将其与局部肺部炎症的指标相关联。这些队列包括具有COPD的HIV感染受试者和在开始抗逆转录病毒之前研究的受试者，并纵向持续了6-12个月。我们还将前瞻性地研究从口咽到肺泡的整个呼吸道的微生物组，以确定上层中发现的内容是否可以预测下呼吸的微生物组。为了实现我们的目标，我们提出以下特定目标。 （1）比较感染HIV的受试者与正常志愿者之间的呼吸道微生物组； （2）直接将HIV感染受试者与正常志愿者中的呼吸微生物组与肺部炎症环境之间的关系相关联； （3）确定高度活性的抗逆转录病毒治疗是否会改变肺微生物组和局部炎症反应； （4）比较了从口咽向肺泡到肺泡的艾滋病毒感染受试者和正常志愿者中的呼吸微生物组。从深度分析开始，将从16s和18s的rRNA测序开始，以描绘出肺中存在的微生物的广阔图片。将对前瞻性鉴定的物种进行详细的宏基因组shot弹枪测序，以表征重要的基因库，这些基因库可能直接影响肺免疫学和炎症环境，这些研究将大大增强我们对健康和疾病中肺部环境的理解，并导致潜在的新模型，从而定义肺部稳态。 相关性（请参阅说明）：在此项目中，我们将检查感染了HIV感染受试者肺中存在的微生物菌群，以确定在发现的生物体类型中它们是否与未感染HIV的受试者之间存在差异。这些研究将增加我们对肺部正常细菌如何影响健康和疾病肺部环境的理解。