부산대학교 도서관

Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV‐induced neuronal cell death remain enigmatic. Here, we report that lytic HSV‐2 infection of human neuron‐like SH‐SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV‐2‐induced GSDME‐mediated cell death occurs downstream of replication‐induced endoplasmic reticulum stress driven by inositol‐requiring kinase 1α (IRE1α), leading to activation of caspase‐2, cleavage of the pro‐apoptotic protein BH3‐interacting domain death agonist (BID), and mitochondria‐dependent activation of caspase‐3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC‐derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress‐driven pathway to execute GSDME‐mediated cell death and promote inflammation. Synopsis: Neurons can be infected by a panel of viruses, but how this induces cell death remains unknown. Here, neuronal cells lytically infected with herpes simplex virus type 2 (HSV‐2) are found to undergo cell death through a mechanism triggered by ER stress and executed by gasdermin E.Lytic HSV‐2 infection in neuronal cells induces gasdermin E‐dependent pyroptosis.ER stress activates caspase‐2 and downstream pro‐apoptotic protein BID cleavage to promote cytoplasmic release of mitochondrial content.Pyroptotic neurons release alarmins to stimulate inflammatory responses via microglia. [ABSTRACT FROM AUTHOR]