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.

项目摘要/摘要 非结核分枝杆菌(NTM)引起一种新出现的、慢性的、具有挑战性的肺部疾病的治疗。 (PD)，其数量现在无可否认地超过了美国的结核病病例(美国)及其他 全球地理区域。众所周知，NTM感染很难根除，而且费用高昂，容易复发。 和再感染，对目前的抗分枝杆菌疗法无效。NTM的环境利基也 在很大程度上仍然是模糊的。这种知识的缺乏导致了人们一直不知道自己在哪里 这些肺部感染是后天的。在美国，夏威夷是NTM PD的地理热点。我们在中国的工作 Hawai‘i发现了丰富的呼吸道重要NTM，包括脓肿分枝杆菌亚种。 家庭和非家庭饮用水中的脓肿、禽分枝杆菌和嵌合体 生物膜和土壤。可能影响夏威夷NTM PD的一个独特的环境因素是暴露在气溶胶中 Kī劳厄火山是地球上喷发最活跃的火山之一。细火山灰 微粒可以被深深地吸入肺部，引起刺激和咳嗽。但是，火山灰有没有可能 也携带传染性NTM吗？通过我们的数据，我们展示了活的脓肿分枝杆菌、禽分枝杆菌、 从2018年Kī劳厄火山喷发期间发现的火山灰和Kī劳厄环境中发现的嵌合体支原体， 支持火山灰作为新描述的NTM的一种类型的可能性。我们证明了KīLauea灰分是 对KīLauea来源的NTM没有直接毒性，而且接触火山灰会减少人巨噬细胞对NTM的控制。 我们项目广泛的、长期的目标是阐明人类使用的先天免疫机制 肺细胞对非结核分枝杆菌感染和气溶胶污染物(如火山灰)的反应，提供了 延伸到夏威夷以外，全世界有数百万人生活在活跃喷发的火山周围几公里内。 在这里，我们利用我们独特的火山灰和从KīLauea火山灰中回收的ntm分离物， KīLauea环境，以及其他夏威夷和非Hawai样品来检验KīLauea灰分的假设 通过拮抗NLRP3炎症小体促进健康肺细胞对NTM感染的控制 上睑下垂防御系统。在这项建议中，我们将：(I)调查KīLauea灰烬的生物学后果 在没有寄主细胞的情况下暴露于KīLauea ntm适合度和(Ii)确定KīLauea ash对 NLRP3炎性小体介导的炎性下垂在人肺泡巨噬细胞清除NTM中的作用 而来自健康捐赠者的气液界面培养的呼吸道上皮细胞，也引入了一种新的3D 尖端外呼吸道上皮类器官培养系统研究Kīlauea NTM和 KīLauea Asch.这项研究的广泛应用将减少围绕着 暴露于具有全球意义的特定环境呼吸污染物，如火山灰影响 在健康的人肺细胞内外的NTM存活，同时告知风险评估 以及应对呼吸道感染和火山灰暴露的治疗干预措施。