{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:21:47Z","timestamp":1773663707975,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,12]]},"group-title":"Immunology","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Type I interferons (IFN-Is), including a single IFN-\u03b2 and over a dozen IFN-\u03b1s, induce the anti-viral state.\n                  <jats:italic>In vitro<\/jats:italic>\n                  , IFN-\u03b2 transcription requires the assembly of the \u201cenhanceosome\u201d composed of the constitutive transcription factors NF-\u03baB and AP-1, and either constitutive IRF3 or IFN-I-inducible IRF7. IRF3 and IRF7 transcribe mouse IFN-\u03b14 and human IFN-\u03b11\/13. Only IRF7 transcribes other IFN-\u03b1s. How IFN-I subtype multiplicity and their differential constitutive\/IFN-I-inducible versus only IFN-I-inducible transcription help control viruses\n                  <jats:italic>in vivo<\/jats:italic>\n                  remains unknown. Using novel genetically modified mice, we demonstrate that most or all IFN-I subtypes, regardless of their transcriptional control, are necessary to curb the systemic dissemination of lymph-borne ectromelia virus (ECTV) but do not necessarily suppress ECTV or West Nile Virus (WNV) replication in the liver or the brain, or promote survival to their infection. Individually, the most critical IFN-I subtype to survive ECTV and WNV infections is IFN-\u03b2. IFN-\u03b14 potentiates IFN-\u03b2 but is not essential. PRDII, the IFN-\u03b2 promoter\u2019s NF-\u03baB binding site, which is required for enhanceosome assembly, is dispensable for\n                  <jats:italic>in vivo<\/jats:italic>\n                  IFN-\u03b2 production but complements IRF7-IFN-\u03b2 transcription to restrain ECTV and WNV. IFN-\u03b2 alone protects IFN-\u03b1-deficient mice from ECTV but not from WNV lethality. Control of WNV replication in the brain successively requires IFN-\u03b1, IFN-\u03b2, and then PRDII-dependent IFN-\u03b2, suggesting that brain protection requires IFN-I production by various cell types and pathways. Thus, contrary to the prevailing view,\n                  <jats:italic>in vivo<\/jats:italic>\n                  , IFN-\u03b2 does not function earlier than IFN-\u03b1, and IFN-I subtypes non-redundantly cooperate to restrain viruses in the periphery and in vital organs.\n                <\/jats:p>","DOI":"10.64898\/2026.03.09.710658","type":"posted-content","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:05:16Z","timestamp":1773324316000},"source":"Crossref","is-referenced-by-count":0,"title":["Interferon-\u03b1 and -\u03b2 subtypes have temporally distinct roles in containing viral spread and protecting vital organs"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0441-5452","authenticated-orcid":false,"given":"Carolina R.","family":"Melo-Silva","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5555-0179","authenticated-orcid":false,"given":"Marisa I.","family":"Roman","sequence":"additional","affiliation":[{"name":"Department of Physics, St Joseph University, Philadelphia PA 19131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7714-1838","authenticated-orcid":false,"given":"Natasha","family":"Heath","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"GlaxoSmithKline, 1250 S. 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