Neurotropism of alphaherpesviruses is most prominent in the mesiotemporal, piriform and prefrontal cortices in mice

Alphaherpesviruses, such as Herpes Simplex Virus 1 (HSV-1) and Pseudorabies Virus (PrV), exhibit pronounced neurotropism. HSV-1 can cause Herpes simplex encephalitis (HSE), primarily affecting the mesiotemporal lobe. CD1 mice inoculated with a PrV mutant (PrV-ΔUL21/US3Δkin) showed striking analogies to HSE, including comparable virus distribution and inflammatory patterns, providing a suitable model to analyze the specificity of the invasion route of alphaherpesviruses. Here, we investigated the strong preference for the mesiotemporal lobe by artificial targeted stereotactic inoculation of PrV-ΔUL21/US3Δkin and wildtype PrV-Kaplan into the temporal lobe or cerebellum in a kinetic approach. In the most severely affected brain areas viral antigen was quantified and correlated with the expression of the alphaherpesvirus entry receptor nectin-1. Temporal lobe inoculated mice showed viral antigen starting at 2dpi in this location. In contrast, only a low amount of viral antigen was found in the cerebellum after cerebellar inoculation but massive staining was observed in the mesiotemporal lobe at 7dpi. Correspondingly, cultured cerebral cortical neurons exhibited higher viral titers than cerebellar neurons, reflecting alphaherpesviral tropism for cerebral regions. Mice inoculated in the temporal lobe developed symptoms earlier than those inoculated into the cerebellum. PrV-Kaplan resulted in rapid lethality within 2 days, with antigen distribution mirroring that of PrV-ΔUL21/US3Δkin. High nectin-1 expression correlated strongly with viral antigen presence in the mesiotemporal lobe, piriform and prefrontal cortices. In summary, our studies demonstrate the high susceptibility of the mesiotemporal, piriform and prefrontal cortices upon artificial PrV inoculation, and highlight the suitability of this model for future investigations on HSE.