SGK1 mediates herpes simplex keratitis via the PI3K/SGK1/ Wnt signaling pathways

Herpes simplex virus type 1 (HSV-1) is a common virus that infects ocular tissues such as the eyelid, cornea, and conjunctiva. Infection of the cornea by HSV-1 causes herpes simplex keratitis (HSK), a condition that can lead to vision loss. Current antiviral treatments for HSV-1 are limited by their action only during active viral replication and by the development of drug resistance.

In this study, we investigated whether the phosphatidylinositol 3′-kinase (PI3K) pathway can regulate serum and glucocorticoid-regulated protein kinase 1 (SGK1) to modulate HSV-1 infection in corneal epithelial cells (CECs).

Our results showed that HSV-1 infection increases viral levels and apoptosis in human corneal epithelial cells (HCECs) and in BALB/c mice.

Whole-transcriptome sequencing, RT-qPCR, and immunofluorescence staining confirmed that SGK1 was upregulated in both infected HCECs and corneal tissues of mice.

Treatment with the SGK1 inhibitor GSK 650394 reduced SGK1 expression, HSV-1 replication, and apoptosis in CECs, as demonstrated by Western blotting, flow cytometry, and in-cell Western blotting. Additionally, HSV-1 infection activated the PI3K pathway in CECs. Inhibition of PI3K with LY294002 resulted in downregulation of both SGK1 and the Wnt signaling protein β-catenin, decreased HSV-1 replication, and reduced apoptosis.

These findings indicate that HSV-1 replication promotes CEC apoptosis through activation of the PI3K/SGK1 signaling pathway, which in turn activates Wnt/β-catenin signaling to further enhance viral replication. Consequently, SGK1 emerges as an important therapeutic target for the treatment of HSK. GSK650394