The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice

Sci Rep. 2021 Oct 27;11(1):21171. doi: 10.1038/s41598-021-00391-7.


Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (RelC307X) that drives lethal HSE in 60% of HSV-1-infected RelC307X mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in RelC307X-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in RelC307X mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Encephalitis, Herpes Simplex / metabolism*
  • Encephalitis, Herpes Simplex / virology
  • Female
  • Interferon Type I / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*
  • Signal Transduction
  • Simplexvirus / genetics
  • Simplexvirus / pathogenicity
  • Simplexvirus / physiology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology


  • Interferon Type I
  • Proto-Oncogene Proteins c-rel