Pulmonary Mycosis Drives FOXA2 Degradation and Mucus Hypersecretion through Activation of the SYK-EGFR-AKT/ERK1/2 Signaling.

ABSTRACT Pulmonary mycoses are difficult to treat and detrimental to patients. Fungal infections modulate the lung immune response, and induce goblet cell hyperplasia and metaplasia, and mucus hypersecretion in the airways. Excessive mucus clogs small airways and reduces pulmonary function by decreasing oxygen exchange, leading to respiratory distress. The Forkhead box protein, FOXA2, is a transcription factor that regulates mucus homeostasis in the airways. However, little is known whether pulmonary mycosis modulates FOXA2 function. Here, we investigated whether Blastomyces dermatitidis and Histoplasma capsulatum-infected canine and feline lungs and airway epithelial cells could serve as higher animal models to examine the relationships between fungal pneumonia and FOXA2-regulated airway mucus homeostasis. The results indicated that fungal infection downregulated FOXA2 expression in airway epithelial cells, with concomitant overexpression of MUC5AC and MUC5B mucins. Mechanistic studies revealed that B. dermatitidis infection, as well as β-glucan exposure, activated the Dectin-1-SYK-EGFR-AKT/ERK1/2 signaling pathway that inhibits the expression of FOXA2, resulting in overexpression of MUC5AC and MUC5B in canine airway cells. Further understanding of the role of FOXA2 in mucus hypersecretion may lead to novel therapeutics against excessive mucus in both human and veterinary patients with pulmonary mycosis.