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.

项目总结/文摘