Mechanisms of «Aspergillus fumigatus» chronic airway disease

Colonization of airways by Aspergillus fumigatus hyphae in immunocompetent patients with chronic lung disease leads to progressive decline in pulmonary function. While a minority of these patients develop a severe allergic response to the fungus, the majority of patients show a decline in lung function and airway hyperreactivity despite the absence of elevated IgE levels, eosinophilia or other evidence of hypersensitivity. Treatment of these non-allergic patients with antifungal drugs improves the symptoms, suggesting that pulmonary complications might be directly caused by A. fumigatus. The mechanisms underlying the acquisition of A. fumigatus colonization and the pathogenesis of pulmonary inflammation have not been studied. Our central hypothesis is that A. fumigatus interacts directly with elements of the immune system to facilitate its own colonization and induces ineffective inflammatory responses that damage host airways. To begin to investigate this hypothesis we used two complementary approaches to examine the interactions of A. fumigatus with elements of the pulmonary immune system. First, we studied the in vitro interactions of A. fumigatus with mast cells, key effector cells involved in orchestrating inflammatory responses and airway reactivity. We found that A. fumigatus triggers mast cell degranulation, while suppressing cytokine expression in an IgE-independent manner. While both degranulation and cytokine transcription required direct contact with mature hyphae, cytokine suppression could also be induced in part by A. fumigatus culture supernatant. Further studies revealed that A. fumigatus hyphae modulated mast cell function by downregulating protein tyrosine phosphorylation and in part by cleavage-dependent activation of protein tyrosine phosphatase 1B (PTP1B). The cleavage of PTP1B was caused by A. fumigatus serine proteases. In parallel, we developed a murine model of A. fumigatus colonization, where airways of healthy mice were colonized with live A. fumigatus by intratracheal injection of conidia embedded within agar beads. Unlike previously described models that induce airway hyperreactivity by repeated challenge with antigen or A. fumigatus spores, infection with this approach resulted in chronic colonization with fungi for up to 28 days. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammation and peribronchial infiltration of lymphocytes. During the first 2 weeks of infection, low level Th2 type responses were seen in the infection, including increased pulmonary IL-4 levels, elevated serum IgE, and a mild increase in airway responsiveness. In addition, significant levels of pro-inflammatory cytokines and chemokines including TNF-α and MIG were observed, suggesting a mixed inflammatory picture. Furthermore, elevated IL-17 levels and presence of RORγ-positive mononuclear cells during late phase of the infection indicated the development of a Th17 response in association with reduction in pulmonary fungal load. Collectively, these results provide insight into the pathogenesis of A. fumigatus-induced chronic airways disease in patients without allergic bronchopulmonary aspergillosis, and suggest a possible role for mast cells in the pathogenesis of this condition.

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