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的发病机制知之甚少。微生物或微生物的移位 由于进入血液循环的产品增加了艾滋病毒的粘膜通透性，刺激了全身 炎症，并与终末器官损伤有关。研究主要集中在移位上。 肠道中的细菌。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)，发生在无侵袭性真菌感染的威斯康星医院。BDG是一种病原体相关分子 激活免疫细胞并引发炎症的模式和真菌细胞壁成分，以及高 在PWH和未感染人群中，全身BDG水平与循环免疫介质相关。我们的 初步数据显示，BDG与HIV患者的肺功能较差有关。在体外，补肾益气颗粒可增加肺 上皮和免疫细胞中炎症介质的表达，提示补肾活血颗粒直接参与了 疾病发病机制。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 循环中的BDG如何与上皮破坏联系在一起，它与宿主真菌微生物群的关系如何，或者如何 BDG铅影响肺功能。在这里，我们测试了HIV(1)中循环BDG起源于 肺真菌菌群在肺通透性受损的情况下，(2)预测更糟糕的呼吸 症状和功能，以及(3)通过影响循环白细胞而导致肺功能受损。使用我们的 建立了匹兹堡HIV肺队列和体外肺模型，我们提出了以下目标：目标1 评估肠道与肺上皮屏障完整性、真菌菌群和循环的关系 威尔斯亲王的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、上皮损伤生物标志物和血浆评估肠和肺的通透性 BDG。我们还将分析呼吸道真菌群落和循环真菌DNA。目标2：实现 研究循环中较高的BDG水平是否预测疾病进展和系统免疫细胞激活 艾滋病慢性阻塞性肺病。我们将检验这样一种假设，即血糖水平较高的重症肝炎患者肺功能较差， 随着时间的推移，呼吸道发病率增加，BDG与肺功能和免疫激活有关。目标3.至 确定补肾活血方是否通过白三烯所致循环免疫细胞中的Dectin-1引起肺部炎症。基于我们的 初步数据，我们假设补肾活血方的主要作用是刺激外周血单核细胞的炎症。 通过Dectin-1受体在HIV的背景下增加生物学影响并将使用 BDG组合，HIV+PBMC条件培养液，Transwell植入井培养模型- 分化的人类呼吸道上皮细胞和最先进的人类肺单芯片小气道。这些 研究调查艾滋病毒相关肺部疾病的全新范例，确定新的治疗方法 目标和生物标记物，并改善对艾滋病毒感染者的护理。

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.