Chronobiology of Neurotropic Viruses: Rhythmic Viral Entry and Arrhythmic Host Clocks

Neurotropic viruses invade neural tissues, resulting in severe diseases such as poliomyelitis, rabies, herpesviral encephalitis, and viral meningitis. Given this neurotropism, we investigated whether the infection of the host by these viruses is under circadian control. Here we show that the expression of most neurotropic virus receptors exhibits rhythmicity across cells, cerebral organoids, and animal models, with host cell susceptibility modulated by the circadian clock. We identify E2F8 as a clock-controlled gene that mediates the indirect regulation of the circadian clock on neurotropic viruses. Notably, E2F8 regulates the expression of core clock components by binding directly to the promoters of REV-ERBa and PER2, suggesting its role as a potential modulator of circadian rhythms. Additionally, we uncovered a seldom-recognized viral strategy to accelerate its own replication in the host: rabies virus disrupts the host circadian clock system primarily through its glycoprotein hijacks the E3 ubiquitin ligase HUWE1 to inhibit proteasomal degradation of REV-ERBa. These findings enhance our understanding of circadian systems' interaction with neurotropic viral dynamics and highlight chronotherapy's potential for improved antiviral treatments. Overall design: CUT&Tag-seq of BMAL1 in Cerebral organoids synchronized with 100 nM hydrocortisone at CT7