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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 (<jats:italic>Rel<\/jats:italic><jats:sup><jats:italic>C307X<\/jats:italic><\/jats:sup>) that drives lethal HSE in 60% of HSV-1-infected <jats:italic>Rel<\/jats:italic><jats:sup><jats:italic>C307X<\/jats:italic><\/jats:sup> mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in <jats:italic>Rel<\/jats:italic><jats:sup><jats:italic>C307X<\/jats:italic><\/jats:sup>-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 <jats:italic>Rel<\/jats:italic><jats:sup><jats:italic>C307X<\/jats:italic><\/jats:sup> mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in <jats:italic>Rel<\/jats:italic><jats:sup><jats:italic>C307X<\/jats:italic><\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41598-021-00391-7","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T10:04:13Z","timestamp":1635329053000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice"],"prefix":"10.1038","volume":"11","author":[{"given":"Mathieu","family":"Mancini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beno\u00eet","family":"Charbonneau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Langlais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia M.","family":"Vidal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"391_CR1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jinf.2016.09.004","volume":"74","author":"LK Jorgensen","year":"2017","unstructured":"Jorgensen, L. 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