Role for NF-κB in herpes encephalitis pathology in mice genocopying an inborn error of IRF3-IFN immunity
Summary
Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1-induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-κB activation. NF-κB inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-κB-driven immunopathology, offering insights with therapeutic potential. © 2025 Idorn et al.
| Authors | Idorn M, Ding X, Fruhwürth S, Holste S, Reinert LS, Skoven CS, Türner-Stenström K, Schmitz A, Vendelbo MH, Ulhøi BP, Vizlin-Hodzic D, Wefelmeyer M, Narita R, Kroese LJ, Huijbers IJ, Møhlenberg M, Hollensen AK, Lai X, Iversen MB, Hansen B, Mogensen TH, Paludan SR |
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| Journal | The Journal of experimental medicine |
| Publication Date | 2026 Jan 5;223(1) |
| PubMed | 41065760 |
| PubMed Central | PMC12510166 |
| DOI | 10.1084/jem.20250064 |