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

摘要：慢性阻塞性肺疾病（COPD）是一个日益严重的健康问题， HIV（PWH）和HIV COPD的机制知之甚少。微生物或微生物的易位 产品进入循环，由于粘膜通透性增加，发生在艾滋病毒，刺激全身 炎症，并与终末器官损伤有关。研究主要集中在 肠道细菌我们和其他人发现真菌易位（通过检测1，3-β-D-葡聚糖来定义） (BDG)在没有侵袭性真菌感染的PWH中发生。BDG是一种病原体相关分子 模式和真菌细胞壁成分，激活免疫细胞，引发炎症，高 全身BDG水平与PWH和未感染人群中的循环免疫介质相关。我们 初步数据显示BDG与HIV患者肺功能恶化有关。在体外，BDG增加肺 上皮细胞和免疫细胞表达炎症介质，表明BDG直接有助于 发病机理虽然这些数据支持真菌易位在HIV COPD中的作用，但我们不知道 BDG如何循环BDG与上皮破坏有关，它如何与宿主真菌微生物组相关，或者如何 BDG电极导线影响肺功能。在这里，我们检验了HIV（1）中循环的BDG来源于 在肺通透性受损的情况下，肺真菌菌群，（2）预测更差的呼吸道疾病， 症状和功能，和（3）通过对循环白细胞的影响导致肺功能受损。使用我们 建立匹兹堡HIV肺队列和体外肺模型，我们提出以下目的：目的1： 评估肠道和肺上皮屏障完整性、真菌菌群和循环之间的关系。 威尔斯亲王医院的BDG水平。我们通过以下方法检验循环BDG起源于肺和肠道的假设： 用功能测定和上皮损伤生物标志物和血浆来评估肠和肺的通透性 BDG。我们还将分析呼吸消化道和循环真菌DNA的真菌群落。目标2： 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活化， 艾滋病慢性阻塞性肺病。我们将检验以下假设：BDG水平较高的PWH肺功能较差， 呼吸道疾病的发病率随着时间的推移，BDG与肺功能和免疫激活有关。目标3。到 确定BDG是否通过来自PWH的循环免疫细胞中的dectin-1引起肺部炎症。基于我们 初步数据显示，我们假设BDG的主要作用是刺激PBMCs的炎症 dectin-1受体在艾滋病毒感染环境中的生物学影响程度增加， BDG的组合、来自HIV+ PBMC的条件培养基、孔- 分化的人气道上皮细胞和最先进的人肺小气道芯片。这些 研究调查了一种全新的HIV相关肺部疾病模式， 目标和生物标志物，并改善艾滋病毒+个人的护理。

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.