TY - JOUR TI - Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1 AU - Cuddy, Sean R AU - Schinlever, Austin R AU - Dochnal, Sara AU - Seegren, Philip V AU - Suzich, Jon AU - Kundu, Parijat AU - Downs, Taylor K AU - Farah, Mina AU - Desai, Bimal N AU - Boutell, Chris AU - Cliffe, Anna R A2 - Brinkmann, Melanie M A2 - Ojala, Päivi M VL - 9 PY - 2020 DA - 2020/12/22 SP - e58037 C1 - eLife 2020;9:e58037 DO - 10.7554/eLife.58037 UR - https://doi.org/10.7554/eLife.58037 AB - Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1β induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1β triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation. KW - herpes simplex virus KW - IL-1 KW - epigenetics KW - dual leucine zipper kinase KW - hyperexcitability JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -