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: 10828133
• 负责人: Jennifer R. Honda
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10828133
• 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.

项目概要/摘要 非结核分枝杆菌 (NTM) 会导致一种新出现的慢性肺部疾病，且治疗具有挑战性 （PD）其数量现在无可否认地超过了美国（U.S.）和其他国家的结核病病例 全球地理区域。根除 NTM 感染非常困难且昂贵，并且容易复发 和再感染，并且对当前的抗分枝杆菌疗法无效。 NTM 的环境利基也 很大程度上仍然是不明确的。这种知识的缺乏导致了持续的挫败感，无法理解在哪里 这些肺部感染是获得性的。在美国，夏威夷是 NTM PD 的地理热点。我们的工作在 夏威夷发现了大量呼吸道重要的 NTM，包括脓肿分枝杆菌亚种。 家庭和非家庭水中的脓肿、鸟分枝杆菌和嵌合分枝杆菌 生物膜和土壤。可能影响夏威夷 NTM PD 的一个独特环境因素是接触气溶胶 来自基拉韦厄火山的污染物，基拉韦厄火山是地球上喷发最活跃的火山之一。细火山灰 颗粒可被吸入肺部深处，引起刺激和咳嗽。但是，火山灰有可能吗？ 也携带传染性NTM？通过我们的数据，我们显示了可行的脓肿分枝杆菌、鸟分枝杆菌、 以及从 2018 年基拉韦厄火山喷发期间回收的火山灰以及基拉韦厄环境中回收的 M. chimaera， 支持火山灰作为新描述的 NTM 污染物的可能性。我们证明基拉韦厄火山灰是 对源自基拉韦厄的 NTM 没有直接毒性，并且灰烬暴露会降低人类巨噬细胞对 NTM 的控制。 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 肺细胞对 NTM 感染和火山灰等气溶胶污染物的反应，提供了以下启示： 范围超出了夏威夷，全世界有数百万人居住在距活跃喷发的火山数公里范围内。 在这里，我们利用了从基拉韦厄火山灰中回收的独特的火山灰和 NTM 分离物集合， 基拉韦厄火山环境以及其他夏威夷和非夏威夷样本，以检验基拉韦厄火山灰的假设 通过拮抗 NLRP3 炎性体介导，加剧健康肺细胞对 NTM 感染的控制 焦亡防御。在本提案中，我们将： (i) 调查基拉韦厄火山灰的生物学后果 在没有宿主细胞的情况下暴露对基拉韦厄 NTM 适应性的影响，以及 (ii) 确定基拉韦厄火山灰对 使用原代人肺泡巨噬细胞清除 NTM 中 NLRP3 炎性体介导的细胞焦亡 和在健康捐赠者的气液界面培养的气道上皮细胞，还引入了一种新的 3D 心尖外气道上皮类器官培养系统，用于研究对 Kīlauea NTM 的先天免疫反应和 基拉韦厄火山灰。该研究的广泛应用将减少围绕如何进行的生物学不确定性 暴露于具有全球意义的特定环境呼吸污染物，例如火山灰的影响 NTM 在健康人肺细胞内外的存活率，同时为风险评估提供信息 针对呼吸道感染和火山灰暴露的治疗干预措施。