Abstract
Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS). However, most individuals intrinsically suppress the virus during a primary infection and preclude it from significantly damaging the CNS. Optineurin (OPTN) is a conserved autophagy receptor with little understanding of its role in neurotropic viral infections. We show that OPTN selectively targets HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy. OPTN-deficient mice challenged with HSV-1 show significant cognitive decline and susceptibility to lethal CNS infection. OPTN deficiency unveils severe consequences for recruitment of adaptive immunity and suppression of neuronal necroptosis. Ocular HSV-1 infection is lethal without OPTN and is rescued using a necroptosis inhibitor. These results place OPTN at the crux of neuronal survival from potentially lethal CNS viral infections.
Highlights
Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS)
When infected with HSV-1 17-strain, Optn−/− mouse embryonic fibroblast (MEF) cells showed significantly more widespread infection (Supplementary Fig. 2D–E). These results were further supported by infection of human corneal epithelial (HCE) cells and Lund human mesencephalic (LUHMES) cells that had been transfected with an siRNA targeting OPTN expression (Supplementary Fig. 1)
We have shown that these mechanisms apply to HSV-1 infection, revealing what is likely an evolutionarily conserved anti-herpesvirus intrinsic cellular defense
Summary
Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS). Immunocompetent individuals are protected, but defects in innate or adaptive immunity may lead to death of infected neurons[6,7]. Selective autophagy is required for specific degradation of damaging cellular occupants and is implicated in protecting the CNS from neurodegenerative diseases[8,9,10]. Evidence supports the protective role of autophagy against protein aggregation in neurons, and it is suggested that it is an innate immune defense mechanism of the CNS19,20. Autophagy has been associated with protection from interferon gamma (IFNγ) and tumor necrosis factoralpha (TNF-α) mediated cell death[25] This potential for selective autophagy to regulate inflammation and cell death may influence the outcome of CNS infections. OPTN deficiency leads to diminished host immune responses to ocular HSV-1 infection, increased susceptibility to herpes encephalitis, and long-term loss of cognition
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