Distinct responses of lung macrophages and airway epithelial cells to Hawai'i-derived volcanic ash and nontuberculous mycobacteria

肺巨噬细胞和气道上皮细胞对夏威夷火山灰和非结核分枝杆菌的独特反应

• 批准号: 10667753
• 负责人: Jennifer R. Honda
• 金额: --
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2023-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667753
• 关键词: 3-Dimensional; Aerosols; Air; Alveolar Macrophages; Antimycobacterial Agents; Apical; Automobile Driving; Behavioral; Binding; Biochemical; Biological; Biological Assay; Cell model; Cells; Chimera organism; Chronic; Collection; Coughing; Data; Defense Mechanisms; Development; Disease; Dust; Elements; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epithelial Cells; Exposure to; Financial cost; Frustration; Genetic; Genomics; Genus Mycobacterium; Geographic Locations; Geography; Goals; Growth; Hawaii; Health Hazards; Hot Spot; Household; Human; Immune; Immune response; Immunologic Factors; Immunologics; Immunology procedure; Impairment; In Vitro; Individual; Infection; Inflammasome; Inhalation; Innate Immune Response; Island; Knowledge; Liquid substance; Lung; Lung diseases; Lung infections; Macrophage; Mediating; Microbial Biofilms; Molecular; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Organism; Organoids; Outcome; Particulate; Pathogenesis; Pathway interactions; Persons; Planet Earth; Predisposition; Prevalence; Prevention; Public Health; Recovery; Refractory; Relapse; Reporting; Research; Research Personnel; Respiratory Disease; Respiratory Tract Infections; Risk Assessment; Role; Sampling; Soil; Surface; System; Testing; Therapeutic Intervention; Tuberculosis; Uncertainty; United States; Virulence Factors; Volcanic Ash; Water; Work; airway epithelium; fitness; genome sequencing; imaging study; improved; innate immune mechanisms; innovation; irritation; non-tuberculosis mycobacteria; opportunistic pathogen; particle; pathogen; pollutant; respiratory; respiratory health; response; transmission process; volcano; whole genome

PROJECT SUMMARY/ABSTRACT Nontuberculous mycobacteria (NTM) cause an emerging, chronic, and challenging to treat pulmonary disease (PD) whose numbers now undeniably surpass tuberculosis cases in the United States (U.S.) and other geographic regions globally. NTM infections are notoriously difficult and expensive to eradicate, prone to relapse and reinfection, and refractory to current anti-mycobacterial therapies. The environmental niches of NTM also remain largely ill-defined. This lack of knowledge contributes to the on-going frustration to understand where these pulmonary infections are acquired. In the U.S., Hawai’i is a geographic hot spot for NTM PD. Our work in Hawai’i revealed an abundance of respiratory important NTM including Mycobacterium abscessus subsp. abscessus, Mycobacterium avium, and Mycobacterium chimaera in household and non-household water biofilms and soil. A unique environmental factor that may impact NTM PD in Hawai’i is exposure to aerosol pollutants from the Kīlauea volcano, one of the most actively erupting volcanoes on Earth. Fine volcanic ash particles can be breathed deep into the lungs causing irritation and cough. But, is it possible for volcanic ash to also carry infectious NTM? Through our data, we show microbiological culture of viable M. abscessus, M. avium, and M. chimaera from ash recovered during the 2018 eruption of Kīlauea and also from the Kīlauea environment, supporting the possibility of volcanic ash as a newly described fomite for NTM. We demonstrate Kīlauea ash is not directly toxic to Kīlauea-derived NTM and that ash exposure reduces NTM control by human macrophages. Our project’s broad, long-term objective is to elucidate the innate immunological mechanisms used by human lung cells in response to NTM infection and aerosol pollutants such as volcanic ash, providing implications that extend beyond Hawai’i with millions of people worldwide living within kilometers of actively erupting volcanoes. Herein, we leverage our unique collection of volcanic ash and NTM isolates recovered from Kīlauea ash, the Kīlauea environment, and other Hawai’i and non-Hawai’i samples to test the hypothesis that Kīlauea ash exacerbates control of NTM infection by healthy lung cells through antagonizing NLRP3 inflammasome-mediated pyroptosis defenses. In this proposal, we will: (i) Investigate the biological consequences of Kīlauea ash exposures on Kīlauea NTM fitness in the absence of host cells and (ii) Determine the effect of Kīlauea ash on NLRP3 inflammasome-mediated pyroptosis in clearance of NTM using primary human alveolar macrophages and airway epithelial cells cultured at the air-liquid interface from healthy donors, but also introduce a new 3D apical out airway epithelial organoid culture system to study innate immune responses to Kīlauea NTM and Kīlauea ash. The study’s broad application will be a reduction in the biological uncertainties surrounding how exposure to specific environmental respiratory pollutants of global significance such as volcanic ash influences NTM survival inside and outside of healthy human lung cells, while simultaneously informing risk assessments and therapeutic interventions in response to respiratory infections and volcanic ash exposures.

项目摘要/摘要 非结核分枝杆菌（NTM）引起出现，慢性和挑战以治疗肺部疾病 （PD）现在，美国（美国）（美国）和其他人的数量不可否认地超过了结核病病例 全球地理区域。 NTM感染非常困难且昂贵，很容易退休 并重新感染，对当前的抗细菌疗法难治性。 NTM的环境利基也 保持不明的定义。缺乏知识有助于持续的挫败感，以了解 这些肺部感染是获得的。在美国，夏威夷是NTM PD的地理热点。我们的工作 夏威夷揭示了呼吸道重要的NTM的抽象，包括脓肿亚科亚州分枝杆菌。 家庭和非家庭水中的脓肿，分枝杆菌和分枝杆菌 生物膜和土壤。可能影响夏威夷NTM PD的独特环境因素是暴露于气雾剂 基拉伊亚火山的污染物是地球上最积极的火山之一。细火山灰 颗粒可以深入肺部，引起刺激和咳嗽。但是，火山灰有可能 还携带感染性NTM吗？通过我们的数据，我们显示了可行的M. Abscessus，M。Avium的微生物培养 在2018年Kīlauea爆发期间，来自Ash的M. Chimaera，也从Kīlauea环境中爆发， 支持火山灰作为NTM的新近描述的火山灰的可能性。我们证明了kīlaueaash是 对Kīlauea衍生的NTM的有毒不直接毒性，并且灰烬暴露会减少人类巨噬细胞的NTM控制。 我们项目的广泛长期目标是阐明人类使用的先天免疫机制 肺细胞应对NTM感染和气溶胶污染物（例如火山灰），这意味着暗示 超越夏威夷，全球数百万的人居住在积极爆发的火山之内。 在此，我们利用了我们从KīlaueaAsh回收的独特的火山灰和NTM分离物的收藏 Kīlauea环境以及其他夏威夷和非霍瓦伊的样品，以测试Kīlaueaash的假设 通过拮抗NLRP3炎症体介导的健康肺细胞对NTM感染的控制加剧 凋亡防御。在此提案中，我们将：（i）研究基拉伊亚灰的生物学后果 在没有宿主细胞的情况下，对kīlaueantm适应性​​的暴露，（ii）确定基拉乌阿灰的影响 NLRP3炎性体介导的凋亡在使用原发性人肺泡巨噬细胞清除NTM时的凋亡 以及在健康供体的空气界面上培养的气道上皮细胞，但也引入了新的3D 顶部的气道上皮器官培养系统，研究对Kīlaueantm的先天免疫反应和 kīlaueaash。该研究的广泛应用将减少围绕如何确定的生物学不确定性 暴露于具有全球意义的特定环境呼吸道污染物，例如火山灰的影响 NTM在健康的人肺细胞内部和外部生存，同时向风险评估提供信息 以及响应呼吸道感染和火山灰的暴露的治疗干预措施。