Murine Models of Repeated Fungal Inhalation Exposure

National Institute Of Environmental Health Sciences

Investigators

Abstract

Adverse health effects have been associated with microbial growth and damp indoor environments; however, knowledge gaps exist as to the mechanisms underlying the responses to fungal exposure. To address these knowledge gaps, NIOSH, in collaboration with the NIEHS, conducted subchronic inhalation studies to examine the pulmonary immunological and toxicological effects following repeated exposure to Aspergillus fumigatus, Stachybotrys chartarum, and Aspergillus versicolor. A computer-controlled acoustical generator system (AGS), based on a modified acoustically powered particle (Pitt-3) generator, was utilized for these studies to model human exposure in a fungal contaminated environment. The overall goal of these studies is to characterize the toxicological and pulmonary responses associated with repeated exposure to fungi commonly found in damp, indoor environments. Previously, a large study assessing the pulmonary and systemic toxicity following repeated exposure to A. versicolor was completed. Data is currently being analyzed for studies conducted in FY23 that measured additional endpoints such as cardiac and respiratory functional assessments. In FY24, analysis of miRNA, mRNA, and proteomic datasets derived from this study will be completed. Increased innate immune cells were observed after 1 week of repeated exposure followed by increasing infiltration of B-cells, T-cells, and type 2 innate lymphoid cells (ILC2s). Following 4 weeks of exposure respiratory impairment, increased local and circulating Th2 cytokines, including IL4 and IL13, as well increased ILC2s was observed. By 13 weeks, cellular infiltration was decreased for all cell types except ILC2s, cardiac function was impaired, and similar to the reported responses following A. fumigatus and S. chartarum exposure, pulmonary arterial tissue remodeling was noted. Additional exposure studies utilizing genetically modified mouse strains have been initiated at NIOSH to characterize specific mechanisms influencing this pulmonary arterial remodeling. Specifically, expression of critical Th2 cytokines involved in pulmonary arterial remodeling, IL4 and IL13, have individually been eliminated in mouse models that are then being used for S. chartarum and A. versicolor exposure studies. These results of these studies utilizing genetically modified mouse models will offer new insight into the mechanisms of pulmonary arterial remodeling and the effect of exposure on extra-pulmonary compartments such as the brain and heart. Recovery following repeated exposure and alterations in neurological inflammatory biomarkers will be investigated in FY24. Basidiomycota yeasts are prominent in indoor contaminated environments but their role in adverse health effects has remained relatively uncharacterized. Studies in mice repeatedly exposed to Cryptococcus victoriae or Cryptococcus neoformans and showed that repeated C. neoformans exposure initiated myeloid and lymphoid cellular infiltration into the lung that worsened over time, whereas repeated V. victoriae exposure induced a strong CD4+ T cell-driven lymphoid response that started to resolve by 21 days post final exposure.