Optineurin is Neuroprotective against Herpes simplex Virus Type-1 Infection

OPTN is a conserved protein that regulates selective autophagy and signaling through ubiquitin binding. Patients with mutations in OPTN often develop glaucoma, amyotrophic lateral sclerosis, or other neurodegenerative diseases. Fast-replicating neurotropic herpesviruses naturally infect the CNS. However, most individuals suppress the virus during a primary infection, preventing potential CNS damage. Using both in vitro and in vivo OPTN knockout and knockdown models, this study presents the first evidence that OPTN is required for restriction of the neurotropic virus, herpes simplex virus-1 (HSV-1). We show that OPTN selectively targeted HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy in vitro. Ocular HSV-1 infection was lethal in vivo for Optn-/- mice. OPTN was required for optimal lymph node activation and T-lymphocyte recruitment and for suppression of neuronal necroptosis. Treatment with a necroptosis inhibitor rescued Optn-/- mice from herpes encephalitis. Examination of ocular pathology revealed that Optn-/- mice rapidly and permanently lose corneal and whisker sensitivity and have more severe herpes keratitis. scRNAseq revealed there is a loss of neuronal activity of Optn-/- animals, and pathway analysis highlighted multiple pathways that may underlie the exacerbated pathology of the PNS following HSV-1 infection. These results place OPTN at the crux of neuronal survival from potentially lethal CNS or PNS viral infections and provide direction for future studies.