The c-Rel transcription factor regulates host defence against neurotropic and cardiac virus infections

Infection with herpes simplex virus 1 (HSV-1) can result in an acute inflammatory condition of the brain called herpes simplex encephalitis (HSE).While relatively rare, HSE is the most common form of sporadic viral encephalitis worldwide.On the other hand, coxsackievirus B3 (CVB3) can establish productive infection in the heart, and is the most frequent cause of viral myocarditis.The onset of both HSE and CVB3-induced myocarditis is influenced in part by host genetics.While the genetic causes of viral myocarditis in humans are unclear, recent studies have established that inborn single gene errors are responsible for disease onset in cases of childhood HSE, where most discovered mutations compromise antiviral type I interferon signaling in the brain.Mouse models of viral infection have been instrumental to define the many layers of genetic regulation that govern host defence responses.To identify novel genetic determinants of HSE that may extend beyond cell-intrinsic interferon signaling, we screened N-ethyl-N-nitrosourea (ENU)-mutagenized mice for susceptibility to HSE, and have discovered a homozygous C307X mutation in the reticuloendotheliosis oncogene (Rel), encoding a premature truncation of the NF-B transcription factor subunit c-Rel, as a cause of lethal encephalitis.Upon HSE symptom onset, moribund mutant mice demonstrated elevated viral replication, neuroinflammation, and cell death in the hindbrain, resulting from defects in cell-mediated immunity.We next applied dual RNA sequencing of both host and viral transcripts, together with flow cytometry, to investigate early effects of the Rel C307X mutation in the HSV-1-infected brain.At least one day prior to symptom onset, mutant brainstems were characterized by elevated viral RNA transcription and by excess interferon-dependent and inflammatory gene expression, predictive of later infiltration of pathological T lymphocytes and myeloid cells that drove fulminant HSE.Thus, Rel C307X -dependent regulation of gene expression in the brain was detrimental in mouse HSE and involves distinct mechanisms from known cases of human childhood HSE.Conversely, the Rel C307X mutation was protective against CVB3-induced myocarditis, resulting in improved control of viral transcription, and a later reduction in infectious CVB3 viral load in the heart.Compared to susceptible wild-type mice, the mutation also resulted in dampened inflammatory and cell-mediated gene expression, suggesting that while T lymphocytes and myeloid cells infiltrated the infected heart, these cells were attenuated in their ability to cause pathological damage to the heart, and allowed the virus to be efficiently cleared.

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