Epidermal Growth Factor Receptor Signaling Governs the Host Inflammatory Response to Invasive Aspergillosis

Area of Science:

• Immunology
• Mycology
• Cell Biology

Background:

• Epidermal growth factor receptor (EGFR) acts as a receptor for fungi like Mucorales and Candida albicans.
• EGFR inhibitors have been linked to invasive aspergillosis in cancer patients, suggesting a protective role for EGFR signaling.
• This contrasts with its role in other fungal infections where EGFR blockade reduces disease severity.

Purpose of the Study:

• To investigate the role of EGFR signaling in host defense against invasive pulmonary aspergillosis caused by Aspergillus fumigatus.
• To determine if EGFR signaling is activated during A. fumigatus infection and its functional consequences.

Main Methods:

• Analysis of transcriptomic data from mouse lungs infected with A. fumigatus.
• Assessment of EGFR activation in human small airway epithelial cells and mouse lungs.
• Inhibition of EGFR using gefitinib in a corticosteroid-induced immunosuppressed mouse model of invasive pulmonary aspergillosis.

Main Results:

• A. fumigatus infection activates genes in the EGFR signaling pathway and EGFR itself in epithelial cells and mouse lungs.
• EGFR signaling in epithelial cells is essential for A. fumigatus endocytosis and pro-inflammatory cytokine production.
• EGFR inhibition in mice led to reduced chemokine levels, decreased phagocyte accumulation, impaired fungal killing, increased fungal burden, and higher mortality.

Conclusions:

• EGFR signaling is indispensable for pulmonary epithelial cells to mount an effective innate immune response against invasive aspergillosis in immunosuppressed hosts.
• EGFR plays a critical protective role in host defense against A. fumigatus lung infections.