PIM1 Inhibition Alleviates Aspergillus fumigatus Keratitis by Regulating DDX41-Mediated STING Signaling Pathway

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• Fungal keratitis (FK) is a severe eye infection with limited treatment options.
• The role of the proto-oncogene PIM1 in FK pathogenesis is unknown.

Purpose of the Study:

• To investigate the role and mechanism of PIM1 in fungal keratitis.
• To explore PIM1's function in human corneal epithelial cells (HCECs) and an Aspergillus fumigatus keratitis mouse model.

Main Methods:

• Assessed PIM1 expression and function using genetic and pharmacologic methods in HCECs and mouse models.
• Analyzed protein interactions and phosphorylation via co-immunoprecipitation and in vitro kinase assays.
• Measured inflammatory cytokine production and signaling pathway activation using ELISA, qRT-PCR, and Western blot.

Main Results:

• Aspergillus fumigatus infection upregulated PIM1 in HCECs and mouse corneas.
• PIM1 enhanced inflammation; PIM1 inhibition reduced pro-inflammatory cytokines.
• PIM1 directly phosphorylated DDX41, activating the STING-TBK1-IRF3 pathway, crucial for PIM1's pro-inflammatory effects.

Conclusions:

• PIM1 aggravates fungal keratitis by activating the DDX41-STING signaling axis.
• PIM1 inhibition alleviated disease severity and fungal load in a mouse model.
• PIM1 represents a potential therapeutic target for fungal keratitis.