Relationship of fungal translocation, inflammation, and pulmonary function in HIV

HIV 中真菌易位、炎症和肺功能的关系

• 批准号: 10483914
• 负责人: Barbara Methe
• 金额: $ 78.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483914
• 关键词: Acute respiratory failure; Aerodigestive Tract; Aerosols; Apical; Biological; Biological Assay; Biological Markers; Biological Response Modifiers; Blood Circulation; C-Type Lectins; Cardiovascular Diseases; Caring; Cell Wall; Cells; Chronic Obstructive Pulmonary Disease; Code; Communities; Data; Dendritic Cells; Detection; Disease; Disease Progression; Epithelial; Epithelial Cells; Fungal DNA; Gene Expression; Genes; HIV; Health; Human; Immune; Impairment; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intestines; Lead; Leukocytes; Link; Lung; Lung diseases; Measures; Microbe; Modeling; Molecular; Mucous Membrane; Mycoses; NF-kappa B; Neurocognitive Deficit; Organ; Outpatients; Pathogenesis; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Permeability; Persons; Phenotype; Plasma; Population; Pulmonary Inflammation; Radionuclide Imaging; Reporter; Respiratory Signs and Symptoms; Respiratory physiology; Role; Signal Transduction; Site; Technology; Testing; Time; Variant; Work; absorption; airway epithelium; antiretroviral therapy; base; cohort; dectin 1; epithelial injury; exposed human population; functional disability; fungus; gut bacteria; immune activation; improved; inflammatory marker; intestinal fatty acid binding protein; microbial; monocyte; mortality; mycobiome; never smoker; new therapeutic target; novel; novel therapeutics; overexpression; pathogen; polyglucosan; prevent; pulmonary function; pulmonary function decline; receptor; receptor for advanced glycation endproducts; respiratory morbidity; sugar; systemic inflammatory response; targeted biomarker; zonulin

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is an increasing health problem in people with HIV (PWH), and mechanisms of HIV COPD are poorly understood. Translocation of microbes or microbial products into the circulation as a result of increased mucosal permeability occurs in HIV, stimulates systemic inflammation, and has been linked to end-organ damage. Studies have largely focused on translocation of bacteria from the gut. We and others find that fungal translocation, defined by detection of 1,3-beta-D-glucan (BDG), occurs in PWH in the absence of invasive fungal infection. BDG is a pathogen-associated molecular pattern and fungal cell wall component that activates immune cells and triggers inflammation, and high systemic BDG levels correlate with circulating immune mediators in PWH and uninfected populations. Our preliminary data show that BDG is associated with worse lung function in HIV. In vitro, BDG increases lung epithelial and immune cell expression of inflammatory mediators, suggesting that BDG contributes directly to disease pathogenesis. While these data support a role of fungal translocation in HIV COPD, we do not know how BDG if circulating BDG is tied to epithelial disruption, how it relates to the host fungal microbiome, or how BDG leads impacts lung function. Here, we test the hypotheses that circulating BDG in HIV (1) originates from the lung fungal mycobiome in the setting of impaired lung permeability, (2) predicts worse respiratory symptoms and function, and (3) leads to impaired lung function via effects on circulating leukocytes. Using our established Pittsburgh HIV Lung cohort and in vitro lung modeling, we propose the following aims: Aim 1: To assess the relationship between gut and lung epithelial barrier integrity, the fungal mycobiome, and circulating BDG levels in PWH. We test the hypothesis that circulating BDG originates in the lung as well as the gut by assessing intestinal and lung permeability with functional assays and epithelial injury biomarkers and plasma BDG. We will also analyze fungal communities of the aerodigestive tract and circulating fungal DNA. Aim 2: To investigate if higher circulating BDG levels predict disease progression and systemic immune cell activation in HIV COPD. We will test the hypothesis that PWH with higher BDG levels have worse lung function and respiratory morbidity over time and that BDG is related to lung function and immune activation. Aim 3. To determine if BDG causes lung inflammation via dectin-1 in circulating immune cells from PWH. Based on our preliminary data, we hypothesize that the primary effect of BDG is from stimulation of inflammation in PBMCs by the dectin-1 receptor with increased magnitude of biological impact in the setting of HIV and will use combinations of BDG, conditioned media from HIV+ PBMCs, transwell insert culture models of well- differentiated human airway epithelial cells, and state-of-the-art Human Lung Small Airway-on-a-Chip. These studies investigate an entirely novel paradigm of HIV-associated pulmonary disease, identify novel therapeutic targets and biomarkers, and improve care of HIV+ individuals.

摘要：慢性阻塞性肺疾病（COPD）是患有患者的健康问题 HIV（PWH）和HIV COPD的机制知之甚少。微生物或微生物的易位 由于HIV中发生粘膜渗透率的增加而导致循环中的产物刺激全身性 炎症，并与最终器官损伤有关。研究主要集中于 肠道的细菌。我们和其他人发现，通过检测1,3-beta-d-glucan定义的真菌易位 （BDG），在没有侵入性真菌感染的情况下发生在PWH中。 BDG是病原体相关的分子 激活免疫细胞并触发炎症的模式和真菌细胞壁成分，高 全身BDG水平与PWH和未感染的人群中的循环免疫介质有关。我们的 初步数据表明，BDG与HIV中的肺功能较差有关。体外，BDG增加肺 炎症介质的上皮和免疫细胞表达，表明BDG直接贡献 疾病发病机理。尽管这些数据支持真菌易位在HIV COPD中的作用，但我们不知道 如果循环BDG与上皮破坏，与宿主真菌微生物组的关系或如何相关，则BDG如何 BDG铅撞击肺功能。在这里，我们测试了艾滋病毒中循环bdg的假设（1）起源于 在肺部渗透性受损的情况下，肺真菌真菌obiome（2）预测呼吸较差 症状和功能，（3）通过对循环白细胞的影响导致肺功能受损。使用我们的 建立的匹兹堡艾滋病毒肺队列和体外肺建模，我们提出以下目的：目标1： 评估肠道和肺上皮屏障完整性，真菌真菌组和循环之间的关系 PWH中的BDG水平。我们检验了循环BDG起源于肺以及肠道的假设 通过功能测定和上皮损伤生物标志物和等离子体评估肠道和肺通透性 BDG。我们还将分析机修区和循环真菌DNA的真菌群落。目标2：到 研究较高的循环BDG水平是否预测疾病进展和全身免疫细胞激活 HIV COPD。我们将检验以下假设：较高BDG水平的PWH具有较差的肺功能和 随着时间的流逝，呼吸道发病率与肺功能和免疫激活有关。目标3 确定BDG是否在PWH的循环免疫细胞中通过Dectin-1引起肺部炎症。基于我们 初步数据，我们假设BDG的主要作用来自PBMC中炎症的刺激 通过Dectin-1受体，在HIV的情况下具有增加生物学影响的幅度，并将使用 BDG的组合，来自HIV+ PBMC的条件培养基，Transwell插入良好的培养模型 分化的人类气道上皮细胞和最先进的人类肺部小型气道。这些 研究研究了一种完全新颖的HIV相关肺疾病的范式，鉴定出新的治疗性 靶标和生物标志物，并改善对艾滋病毒+个体的护理。