LAUSR

ABSTRACT Very little is known about the mechanisms that restrict neurotropic herpesviruses such as herpes simplex virus-1 (HSV-1) from infecting the central nervous system (CNS) and causing widespread death of neurons. Likewise, HSV-1 is thought to play a role in chronic neurodegeneration, yet a direct association has remained elusive. To address these issues, we recently showed that the selective macroautophagy/autophagy receptor OPTN (optineurin) specifically targets HSV-1 proteins VP16 and gB for degradation to prevent viral spread in the brain. OPTN deficiency alters host cytokine expression and tissue-specific immune signaling, and enhances necroptotic death of infected neurons. HSV-1-infected optn knockout mice show higher susceptibility to lethal CNS infection and the surviving animals demonstrate cognitive deficiency. Our research suggests that OPTN-mediated autophagy provides an intrinsic immune barrier against neurotropic viruses and protects the CNS from neurodegenerative stress.