Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis

Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae. HSV-1 Infection causes severe Neurological Disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces Ferroptosis in the CNS and the role of Ferroptosis in viral pathogenesis remain unclear. Here, we demonstrate that HSV-1 induces Ferroptosis, as hallmarks of Ferroptosis, including Fe²⁺ overload, Reactive Oxygen Species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, and mitochondrion shrinkage, are observed in HSV-1-infected cultured human astrocytes, microglia cells, and murine brains. Moreover, HSV-1 Infection enhances the E3 ubiquitin Ligase Keap1 (Kelch-like ECH-related protein 1)-mediated ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidative genes, thereby disturbing cellular redox homeostasis and promoting Ferroptosis. Furthermore, HSV-1-induced Ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin E₂ (PGE₂) plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of Ferroptosis by a Ferroptosis inhibitor or a Proteasome Inhibitor to suppress Nrf2 degradation effectively alleviated HSV-1 encephalitis. Together, our findings demonstrate the interaction between HSV-1 Infection and Ferroptosis and provide novel insights into the pathogenesis of HSV-1 encephalitis. IMPORTANCE Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces Ferroptosis in the CNS and the role of Ferroptosis in viral pathogenesis remain unclear. In the current study, we demonstrate that HSV-1 Infection induces Ferroptosis, as Fe²⁺ overload, ROS accumulation, GSH depletion, lipid peroxidation, and mitochondrion shrinkage, all of which are hallmarks of Ferroptosis, are observed in human cultured astrocytes, microglia cells, and murine brains infected with HSV-1. Moreover, HSV-1 Infection enhances Keap1-dependent Nrf2 ubiquitination and degradation, which results in substantial reductions in the expression levels of antiferroptotic genes downstream of Nrf2, thereby disturbing cellular redox homeostasis and promoting Ferroptosis. Furthermore, HSV-1-induced Ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of PTGS2 and PGE₂ plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of Ferroptosis by either a Ferroptosis inhibitor or a Proteasome Inhibitor to suppress HSV-1-induced Nrf2 degradation effectively alleviates HSV-1-caused neuro-damage and inflammation in infected mice. Overall, our findings uncover the interaction between HSV-1 Infection and Ferroptosis, shed novel LIGHT on the physiological impacts of Ferroptosis on the pathogenesis of HSV-1 Infection and encephalitis, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution.

HSV-1; Nrf2-Keap1; PTGS2/PGE2; ferroptosis; viral encephalitis.