# Spatial and temporal mapping of early alphaherpesvirus invasion routes into the mouse central nervous system

## TL;DR

This study maps how alphaherpesviruses like HSV-1 and PrV enter the mouse central nervous system through multiple nerves, including olfactory and trigeminal pathways.

## Contribution

The study identifies new cranial nerve routes for alphaherpesvirus neuroinvasion using a PrV mutant in mice.

## Key findings

- Viral antigens and gene expression were detected in the olfactory epithelium, vomeronasal organ, and brainstem.
- Multiple cranial nerves (I, V, IX, XII) were identified as routes for early alphaherpesvirus CNS invasion.
- The PrV-∆UL21gfp/US3∆kin mutant model is valuable for studying early viral spread in the nervous system.

## Abstract

Alphaherpesviruses such as Herpes Simplex Virus 1 (HSV-1) and Pseudorabies virus (PrV) invade the central nervous system (CNS) via peripheral nerves. While olfactory and trigeminal pathways are well-known, additional cranial routes remain underexplored. Using a PrV-∆UL21gfp/US3∆kin mutant in CD1 mice, we mapped early neuroinvasion (4–96 hpi) by immunofluorescence and RNA in situ hybridization. Viral antigen and lytic viral gene expression (UL19 RNA) were detected in the olfactory epithelium, vomeronasal organ, incisors, palate, olfactory bulb, and brainstem. These results indicate multineural CNS access involving olfactory (I), trigeminal (V), glossopharyngeal (IX), and hypoglossal (XII) nerves, highlighting this model’s value for studying early alphaherpesvirus spread.

The online version contains supplementary material available at 10.1007/s13365-025-01278-3.