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

Herpes simplex virus type 1 (HSV-1) is a common virus infecting the ocular tissue. It infects eye tissues, such as the eyelid, cornea, and conjunctiva. Corneal HSV-1 infection causes herpes simplex keratitis (HSK), which can induce vision loss. Current treatments for eye infections targeting HSV-1 can led to various sequelae. Antiviral drugs only work during active viral replication, and viral resistance has been recorded in numerous cases. Therefore, it is necessary to determine the molecular mechanisms underlying HSV-1 infection and identify new antiviral drugs. There are no reports on whether PI3K can regulate SGK1 to modulate HSV-1 infection in corneal epithelial cells (CECs), or how this mechanism works. This study found that HSV-1 levels and apoptosis increased in human corneal epithelial cells (HCECs) and BALB/c mice after HSV-1 infection. Serum and glucocorticoid-regulated protein kinase 1 (SGK1) were upregulated in HCECs and corneal tissues of BALB/c mice infected with HSV-1, as evidenced by whole-transcriptome sequencing, quantitative real-time polymerase chain reaction (RT-qPCR), and immunofluorescence staining experiments. An inhibitor of SGK1 (GSK 650394) reduced SGK1 expression, HSV-1 replication, and apoptosis in CECs, as evidenced by western blotting, flow cytometry, and in cell western blotting. The phosphatidylinositol 3'-kinase (PI3K) pathway was activated in CECs infected with HSV-1. After treatment with the PI3K inhibitor (LY294002), the expression of SGK1 and Wnt signaling pathway protein β-catenin were downregulated, and the replication of HSV-1 decreased in CECs; additionally, CECs apoptosis was reduced. HSV-1 replication causes CECs apoptosis. In HSV-1 infected CECs, SGK1 expression was upregulated by activated PI3K/SGK1 signaling pathway. Additionally, SGK1 activated Wnt/β-catenin signaling pathway to promote HSV-1 replication and cause CEC apoptosis. In conclusion, SGK1 is an important target for HSK treatment.