Investigating the role of altered lung microbiome in fueling Th17 mediated airway inflammation in COPD among HIV-infected individual

研究肺部微生物组改变在 HIV 感染者 COPD 中促进 Th17 介导的气道炎症的作用

• 批准号: 10872354
• 负责人: Alex Kayongo
• 金额: $ 10万
• 依托单位: MAKERERE UNIVERSITY COLLEGE OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10872354
• 关键词: Acceleration; Affect; Africa South of the Sahara; Age; Aging; Attention; Bronchoalveolar Lavage; Bronchoscopy; Catalogs; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Data; Deterioration; Development; Disease; Distal; Elderly; Enzyme-Linked Immunosorbent Assay; Exposure to; General Population; Genes; HIV; HIV Infections; Health Sciences; Immune; Immunology; Individual; Infection; Inflammaging; Inflammation; Instruction; Interleukin-6; Irrigation; Laboratories; Life Expectancy; Light; Longevity; Lung; Manufacturer; Measures; Mediating; Molecular; Morbidity - disease rate; Outcome; Parents; Participant; Pattern; Persons; Population; Predisposition; Prevalence; Probability; Procedures; Process; Protocols documentation; Pulmonary Function Test/Forced Expiratory Volume 1; RNA; Role; Running; Rural; Sampling; Shortness of Breath; Students; Survivors; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; TNF gene; Testing; Uganda; Universities; Viral; age related; airway inflammation; antiretroviral therapy; cDNA Library; cohort; college; cytokine; density; disorder control; exhaustion; experience; fighting; functional decline; immune activation; immunological diversity; immunosenescence; indexing; lung microbiome; mortality; pathogen; preference; preservation; pulmonary function; pulmonary function decline; research and development; senescence; sequencing platform; timeline

Abstract Chronic Obstructive Pulmonary Disease (COPD) is increasing in prevalence among people living with HIV (PLWH) as the widespread use of antiretroviral therapy (ART) has increased longevity in this population. With the highest density of PLWH, Sub-Saharan Africa has experienced dramatic increases in COPD-related morbidity and mortality. Despite viral suppression, it’s not fully known what drives accelerated lung function decline in this population. Amidst intense exposure to environmental insults, the airways have developed robust protective mechanisms which preserve the airway microenvironment, with highly specialized lung-resident innate and adaptive immune cells fighting off pathogens. However, these protective mechanisms deteriorate with age, resulting in a progressive decline in lung function and COPD development. This decline is worse in the setting of chronic HIV infection. Despite a lack of conclusive evidence, persistent airway immune activation among PLWH possibly drives airway immunosenescence, inflammaging, and progressive lung function decline. It is probable that in the setting of chronic HIV, contraction of the T-cell immune repertoire (immune diversity) increases susceptibility to infections, which drives chronic inflammation, immune exhaustion, and senescence. In this supplementary application, we aim to investigate the effect of HIV on distal airway immunosenescence and inflammaging among individuals with COPD. We hypothesize that: (1) chronic HIV infection accelerates age-dependent contraction of airway T cell receptor diversity; (2) and this reduced diversity is associated with airway inflammation and poor lung function (low FEV1 and FVC). We will use broncho-alveolar lavage samples from our currently running parent R21 study to; (1) determine the effect of chronic HIV on airway TCR diversity and (2) correlate airway TCR diversity indices with levels of inflammaging cytokines in BAL supernatant. This preliminary data will provide a basis to investigate airway inflammaging among PLWH, supplementing our parent R21 objectives of investigating the association between lung microbiome and immune profile in the distal airways of HIV-infected individuals with COPD in a viremically controlled Ugandan HIV cohort.

摘要 慢性阻塞性肺疾病(COPD)在艾滋病毒携带者中的患病率正在上升 (PLWH)，因为抗逆转录病毒疗法(ART)的广泛使用延长了这一人群的寿命。使用 PLWH密度最高的撒哈拉以南非洲地区与COPD相关的人数急剧增加 发病率和死亡率。尽管病毒受到抑制，但目前还不完全清楚是什么原因导致肺加速 这一人群的机能衰退。在强烈的环境侮辱中，航空公司 开发了强大的保护机制，以保护呼吸道微环境，具有高度专业化 居住在肺部的先天和获得性免疫细胞对抗病原体。然而，这些保护机制 随着年龄的增长而恶化，导致肺功能进行性下降和慢性阻塞性肺病的发展。这一下降是 更糟糕的是在慢性艾滋病毒感染的背景下。尽管缺乏确凿证据，但持续性呼吸道免疫 PLWH的激活可能导致呼吸道免疫衰老、炎症和进展性肺 功能衰退。很可能在慢性HIV感染的背景下，T细胞免疫谱系的收缩 (免疫多样性)增加感染的易感性，从而推动慢性炎症，免疫 精疲力竭和衰老。在这个补充应用中，我们的目的是研究HIV对远端的影响。 慢性阻塞性肺疾病患者的呼吸道免疫衰老和炎症反应。我们假设：(1)慢性 HIV感染加速了呼吸道T细胞受体多样性与年龄相关的收缩；(2)这 多样性降低与呼吸道炎症和肺功能差(FEV1和FVC低)有关。 我们将使用目前正在进行的母公司R21研究中的支气管肺泡灌洗样本；(1)确定 慢性HIV对呼吸道TCR多样性的影响及(2)气道TCR多样性指数与水平的相关性 BAL上清液中的致炎细胞因子。这一初步数据将为研究呼吸道提供依据 在PLWH中引发炎症，补充我们的父代R21目标，调查两者之间的关联 病毒感染的慢性阻塞性肺疾病患者远端呼吸道的肺微生物群和免疫状态 受控制的乌干达艾滋病毒队列。