# Chronobiology of neurotropic viruses: rhythmic viral entry and arrhythmic host clocks

## TL;DR

This paper explores how neurotropic viruses interact with the body's circadian clock, revealing new insights into viral entry and replication.

## Contribution

The study identifies E2F8 as a clock-controlled gene and reveals a novel viral strategy involving rabies virus disrupting the circadian clock via HUWE1.

## Key findings

- Expression of neurotropic virus receptors shows rhythmicity modulated by the circadian clock.
- E2F8 regulates core clock components by binding to REV-ERBα and PER2 promoters.
- Rabies virus accelerates replication by hijacking HUWE1 to inhibit REV-ERBα degradation.

## Abstract

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. In this study, we found 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 identified E2F8 as a clock-controlled gene that mediates the indirect regulation of the circadian clock on neurotropic viruses. Notably, E2F8 regulated the expression of core clock components by binding directly to the promoters of REV-ERBα and PER2, suggesting its role as a potential modulator of circadian rhythms. Additionally, we revealed a seldom-recognized viral strategy to accelerate viral replication in the host: rabies virus disrupts the host circadian clock system primarily through its glycoprotein hijacking the E3 ubiquitin ligase HUWE1 to inhibit proteasomal degradation of REV-ERBα. These findings increase our understanding of the interactions between circadian systems and neurotropic viral dynamics and highlight the potential of chronotherapy for improved antiviral treatments.