Herpes simplex encephalitis (HSE) is a devastating condition of the central nervous system (CNS) resulting from infection with herpes simplex virus 1 (HSV-1). Studies in humans and mice have shown that susceptibility to HSE depends in part on the genetic make-up of the host.

To identify new host factors involved in HSE susceptibility, we have implemented a genome-wide N-Ethyl-N-nitrosourea (ENU) mutagenesis screen in an in vivo HSV-1 mouse model. In one pedigree, whole exome sequencing led to the identification of a chemically-induced mutation in the Rel gene causing increased susceptibility to HSV-1. This C307X nonsense mutation introduced a premature stop codon in the encoded c-Rel protein, one of five subunits of the NF-kB transcription factor.

The HSE-susceptible phenotype of Rel^C307X mice has been validated in both intraperitoneal and intranasal models of HSV-1 infection, and is characterized by high viral replication and hyperinflammation in CNS tissue. Rel^C307X expresses a truncated c-Rel protein which retains its conserved amino-terminal DNA binding domain. Rel^C307X mice have significantly fewer peripheral and thymic CD4⁺Foxp3⁺ regulatory T (Treg) cells compared to wild type animals, at both steady-state and during infection. The Treg compartment may promote protective immunity to HSE by ensuring control of lethal hyperinflammation in the infected CNS.

This study will provide valuable insight into the genetic etiology of HSE. Furthermore, the mechanics of immune effector and regulatory cells in Rel^C307X mice may point to novel therapeutic strategies for neuro-inflammatory disorders.