Anti-Aspergillus Activities of the Respiratory Epithelium in Health and Disease

Abstract

Abstract:Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of Aspergillus fumigatus. Inhaled Aspergillus spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of Aspergillus-epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of Aspergillus spores as either a curative or disease-exacerbating event.

Lung colonization by Aspergillus fumigatus is controlled by ZNF77

“…Besides physical removal by mucociliary flow, epithelial cells can secrete a wide range of antimicrobial peptides and they can also act as non-professional phagocytes 22 . Moreover, they secrete chemotactic factors to recruit more specialized immune cells to contribute to fungal clearance 23 . Most clearance mechanisms mediated by epithelium and macrophages are effective against ungerminated conidia.…”

“…Early after inhalation, A. fumigatus conidia will contact the airway epithelium where they swell and germinate to form hyphae. Native and swollen spores can be internalized before undergoing germination and hyphal growth within epithelial cells 23 . Moreover, factors secreted by epithelial cells (defensins, PTX3, etc.)…”

Three-Dimensional Light Sheet Fluorescence Microscopy of Lungs To Dissect Local Host Immune-Aspergillus fumigatus Interactions

“…For example, elastase has been disregarded as a virulence factor in A. fumigatus (53), but that could be because degrading elastin might be more relevant in the alveoli, where elastin is readily present in the alveolar wall. Besides, the first contact with the host is not orchestrated exclusively by alveolar epithelial cells, such as is normally assumed in humans (54). It is nevertheless important that there are morphological differences between the human and the murine respiratory tracts, with particularly enormous differences in the spatial dimensions, e.g., the distance from the nasal/oral cavities to the tracheobronchial tree or to the surface of an alveolus, which is approximately 20-fold smaller in a murine alveolus (55) than in a human alveolus (estimated mean alveolar volume measures of only Ͻ5.95 ϫ 10 4 m 3 in mice [56] compared to 4.2 ϫ 10 6 m 3 in humans [57]).…”

3D light sheet fluorescence microscopy of lungs to dissect local host immune -Aspergillus fumigatusinteractions

“…For example, elastase has been disregarded as a virulence factor in A. fumigatus [56], but that could be because degrading elastin might be more relevant in the alveoli, where elastin is readily present in the alveolar wall. Besides, the first contact with the host will not be orchestrated exclusively by alveolar epithelial cells, as it is normally assumed in humans [57]. Additionally, in vivo murine studies may result in underestimating the role of AMs for human infection [49].…”