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Many of these viruses, including flaviviruses, herpesviruses, rhabdoviruses and alphaviruses enter the brain through the olfactory neuroepithelium (ONE) in the olfactory bulbs (OB). Due to the low percentage of encephalitis that occurs following these infections, it\u2019s thought that OBs have specialized innate immune responses to eliminate viruses. Murine hepatitis virus strain JHM (JHMV) is a model coronavirus that causes severe encephalitis and can access the brain through olfactory sensory neurons. We\u2019ve shown that a JHMV Mac1-mutant virus, N1347A, has decreased replication and disease in the brains of mice. Here we further show that this virus replicates poorly in the OB. However, it is unknown which innate immune factors restrict N1347A replication in the OB. RNA-seq analysis of infected olfactory bulbs showed that IFN\u03b3 was upregulated in the OB while IFN-\u03b2 was barely detectable at 5 days post-infection. To determine if IFN-\u03b3 restricts JHMV N1347A replication, we utilized IFN-\u03b3 and IFN-\u03b3 receptor (IFN-\u03b3R) knockout (KO) mice. Surprisingly we found that JHMV WT and N1347A replicated very poorly in the OB and whole brains of both IFN-\u03b3 and IFN-\u03b3R KO mice following intranasal infection, though survival and weight loss were unaltered. Furthermore, we determined that microglia, macrophages, and CD4\u2009+\u2009T cells were the primary cells producing IFN-\u03b3 during the early stages of this infection. We conclude that IFN-\u03b3 is required for the efficient replication of JHMV in the brains of infected mice.<\/jats:p>","DOI":"10.1371\/journal.pone.0317482","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T17:37:03Z","timestamp":1749145023000},"page":"e0317482","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["IFN-\u03b3 signaling is required for the efficient replication of murine hepatitis virus (MHV) strain JHM in the brains of infected mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Catherine M.","family":"Kerr","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Macie 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