Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi

Abstract

Active fungal proteinases are powerful allergens that induce experimental allergic lung disease strongly resembling atopic asthma, but the precise relationship between proteinases and asthma remains unknown. Here, we analyzed dust collected from the homes of asthmatic children for the presence and sources of active proteinases to further explore the relationship between active proteinases, atopy, and asthma. Active proteinases were present in all houses and many were derived from fungi, especially Aspergillus niger. Proteinase-active dust extracts were alone insufficient to initiate asthma-like disease in mice, but conidia of A. niger readily established a contained airway mucosal infection, allergic lung disease, and atopy to an innocuous bystander antigen. Proteinase produced by A. niger enhanced fungal clearance from lung and was required for robust allergic disease. Interleukin 13 (IL-13) and IL-5 were required for optimal clearance of lung fungal infection and eosinophils showed potent anti-fungal activity in vitro. Thus, asthma and atopy may both represent a protective response against contained airway infection due to ubiquitous proteinase-producing fungi.

Necessary and Sufficient Role for T Helper Cells To Prevent Fungal Dissemination in Allergic Lung Disease

“…A. niger conidia administered at relatively low exposure doses consistently induce a highly polarized Th2 response, allergic inflammation, and asthma-like disease in mice (45). This observation appears inconsistent with the prior results of Aimanianda et al, who reported that dormant conidia of a closely related organism, A. fumigatus, elicited little or no inflammation when administered to cultured dendritic cells and mice in vivo (3).…”

“…All studies were performed 24 h after the final i.n. conidium challenge as previously described (45).…”

“…We previously demonstrated that the conidia of the ubiquitous fungus Aspergillus niger, given in relatively small amounts, trigger a highly polarized Th2-predominant allergic response in mice that provokes canonical features of asthma, including airway hyperreactivity, robust airway eosinophilia, and goblet cell metaplasia with mucus hypersecretion (45). We further demonstrated that in addition to macrophages and neutrophils, eosinophils also have potent antifungal properties.…”

“…Fungal airway infections are also linked to a spectrum of T helper (Th) cell responses, including Th1, Th2, and Th17 cell activation (4,8,26,39,45). We previously demonstrated that the conidia of the ubiquitous fungus Aspergillus niger, given in relatively small amounts, trigger a highly polarized Th2-predominant allergic response in mice that provokes canonical features of asthma, including airway hyperreactivity, robust airway eosinophilia, and goblet cell metaplasia with mucus hypersecretion (45).…”

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

“…First, serological studies in patients with ABPA and SAFS demonstrate IgE responses to fungal products derived from in vivo germination of inhaled conidia into hyphae, as these antibodies exist as a response to fungal exoproducts, hyphal cell wall components expressed during growth phase and cytoplasmic antigens [21,22]. Secondly, there is mounting evidence that fungal hyphal products, including b-glucan and proteases, activate epithelial cells to secrete proinflammatory and Th2-polarising cytokines and chemokines directly via Toll-like receptor-induced signalling, via other innate sensors or via protease-activated receptors [23][24][25][26]. Thirdly, fungal asthma has been linked to host innate immune responses to chitin, a major fungal cell wall component, as chitinase promoter polymorphisms and associated alterations in chitinase activity and elevated chitinase-like protein YKL-40 levels have been found in SAFS in adults and children [27][28][29][30][31][32][33].…”