{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:30:37Z","timestamp":1789047037461,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,8]]},"group-title":"Immunology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["RO1AI157201"],"award-info":[{"award-number":["RO1AI157201"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,8]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>The gammaherpesviruses, including Epstein-Barr Virus and Kaposi\u2019s Sarcoma-associated Herpesvirus, establish lifelong infections by maintaining a balance between lytic and latent infection states. How this balance is regulated in myeloid cells, an important but understudied cell type that can achieve both infection states, remains unclear. Using the murine gammaherpesvirus 68 (MHV68) model, we show that IFN\u03b3 and IL-4 reciprocally regulate lytic infection in macrophages in a time- and JAK\/STAT signaling dependent-manner, with basal JAK\/STAT signaling further restricting lytic infection. Using a combination of MHV68 reporter viruses, cellular and molecular techniques, we demonstrate that IFN\u03b3 blocks lytic replication through at least two distinct mechanisms, restricting delivery to or stability of the viral genome in the nucleus and potently restricting lytic cycle progression downstream of the immediate-early viral transactivator, RTA. These findings define specific points during lytic infection where IFN\u03b3 to enforce restricted, latent-like infection in myeloid cells.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"749271v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>IL-4 and IFN\u03b3 reciprocally regulate MHV68 macrophage infection in a time-dependent manner<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Lytic replication is induced by the JAK1\/JAK2 inhibitor Ruxolitinib<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>IFN\u03b3 regulates MHV68 infection at two distinct stages<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>IFN\u03b3 pre-treatment limits viral nuclear entry<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.03.749271","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:55:12Z","timestamp":1788911712000},"source":"Crossref","is-referenced-by-count":0,"title":["Cytokine signaling regulates multiple stages of gammaherpesvirus infection in myeloid cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6529-3831","authenticated-orcid":false,"given":"Rachael E.","family":"Kostelecky","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-3013","authenticated-orcid":false,"given":"Gabrielle","family":"Vragel","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3210-9690","authenticated-orcid":false,"given":"Pedro","family":"Gamez","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-0213","authenticated-orcid":false,"given":"Eva M.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Denver Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2090-7489","authenticated-orcid":false,"given":"Darby G.","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"Gundersen Medical Foundation, Emplify Health System, La Crosse, WI 54601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-7128","authenticated-orcid":false,"given":"Andrew","family":"Goodspeed","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, | Anschutz Medical Campus, School of Medicine, Aurora, CO, 80045, USA"},{"name":"University of Colorado Cancer Center, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, CO, 80045, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0862-4883","authenticated-orcid":false,"given":"Christoph","family":"Weigel","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1619-4853","authenticated-orcid":false,"given":"Robert A.","family":"Baiocchi","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-9544","authenticated-orcid":false,"given":"Eric T.","family":"Clambey","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-5554","authenticated-orcid":false,"given":"Linda F.","family":"van Dyk","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091006000642000_2026.09.03.749271v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-021-03824-y"},{"key":"2026091006000642000_2026.09.03.749271v1.2","doi-asserted-by":"crossref","unstructured":"Dong, S. , Forrest, J. C. & Liang, X. in Infectious Agents Associated Cancers: Epidemiology and Molecular Biology (eds Qiliang Cai , Zhenghong Yuan , & Ke Lan ) 225\u2013236 (Springer Singapore, 2017).","DOI":"10.1007\/978-981-10-5765-6_14"},{"key":"2026091006000642000_2026.09.03.749271v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj8222"},{"key":"2026091006000642000_2026.09.03.749271v1.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-011921-082615"},{"key":"2026091006000642000_2026.09.03.749271v1.5","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9020125"},{"key":"2026091006000642000_2026.09.03.749271v1.6","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-025-02779-7"},{"key":"2026091006000642000_2026.09.03.749271v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s40588-024-00214-z"},{"key":"2026091006000642000_2026.09.03.749271v1.8","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.656979"},{"key":"2026091006000642000_2026.09.03.749271v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.4.3273-3283.1999"},{"key":"2026091006000642000_2026.09.03.749271v1.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002935"},{"key":"2026091006000642000_2026.09.03.749271v1.11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.7.3828"},{"key":"2026091006000642000_2026.09.03.749271v1.12","doi-asserted-by":"publisher","DOI":"10.1101\/2023.06.21.545948"},{"key":"2026091006000642000_2026.09.03.749271v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01452-1"},{"key":"2026091006000642000_2026.09.03.749271v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0029-z"},{"key":"2026091006000642000_2026.09.03.749271v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl2016"},{"key":"2026091006000642000_2026.09.03.749271v1.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254517"},{"key":"2026091006000642000_2026.09.03.749271v1.17","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01946-20"},{"key":"2026091006000642000_2026.09.03.749271v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00108-07"},{"key":"2026091006000642000_2026.09.03.749271v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.1.192-200.2006"},{"key":"2026091006000642000_2026.09.03.749271v1.20","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.14.7125-7132.2002"},{"key":"2026091006000642000_2026.09.03.749271v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nm1297-1346"},{"key":"2026091006000642000_2026.09.03.749271v1.22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0291"},{"key":"2026091006000642000_2026.09.03.749271v1.23","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00989-09"},{"key":"2026091006000642000_2026.09.03.749271v1.24","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2011.0004"},{"key":"2026091006000642000_2026.09.03.749271v1.25","unstructured":"Staudt, M. R. & Dittmer, D. P. in Kaposi Sarcoma Herpesvirus: New Perspectives (eds Chris Boshoff & Robin A. Weiss ) 71\u2013100 (Springer Berlin Heidelberg, 2007)."},{"key":"2026091006000642000_2026.09.03.749271v1.26","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02099-09"},{"key":"2026091006000642000_2026.09.03.749271v1.27","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00396-10"},{"key":"2026091006000642000_2026.09.03.749271v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.08.019"},{"key":"2026091006000642000_2026.09.03.749271v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.04.008"},{"key":"2026091006000642000_2026.09.03.749271v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004556"},{"key":"2026091006000642000_2026.09.03.749271v1.31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00060-10"},{"key":"2026091006000642000_2026.09.03.749271v1.32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.17.9215-9223.2004"},{"key":"2026091006000642000_2026.09.03.749271v1.33","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02572-09"},{"key":"2026091006000642000_2026.09.03.749271v1.34","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02689-07"},{"key":"2026091006000642000_2026.09.03.749271v1.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611228113"},{"key":"2026091006000642000_2026.09.03.749271v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.08.004"},{"key":"2026091006000642000_2026.09.03.749271v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.048"},{"key":"2026091006000642000_2026.09.03.749271v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09152-2"},{"key":"2026091006000642000_2026.09.03.749271v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-022-01380-6"},{"key":"2026091006000642000_2026.09.03.749271v1.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007838"},{"key":"2026091006000642000_2026.09.03.749271v1.41","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000490"},{"key":"2026091006000642000_2026.09.03.749271v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bneo.2026.100200"},{"key":"2026091006000642000_2026.09.03.749271v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.09.024"},{"key":"2026091006000642000_2026.09.03.749271v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2007.05.008"},{"key":"2026091006000642000_2026.09.03.749271v1.45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011691"},{"key":"2026091006000642000_2026.09.03.749271v1.46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004761"},{"key":"2026091006000642000_2026.09.03.749271v1.47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000935"},{"key":"2026091006000642000_2026.09.03.749271v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpt.2025.12.001"},{"key":"2026091006000642000_2026.09.03.749271v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bneo.2024.100053"},{"key":"2026091006000642000_2026.09.03.749271v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.016"},{"key":"2026091006000642000_2026.09.03.749271v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.023"},{"key":"2026091006000642000_2026.09.03.749271v1.52","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000140"},{"key":"2026091006000642000_2026.09.03.749271v1.53","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.9.7658-7670.1999"},{"key":"2026091006000642000_2026.09.03.749271v1.54","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.8.5894-5904.1997"},{"key":"2026091006000642000_2026.09.03.749271v1.55","unstructured":"Wickham, H . ggplot2: Elegant Graphics for Data Analysis. 2nd 2016 edn, (Springer Nature, 2016)."},{"key":"2026091006000642000_2026.09.03.749271v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"2026091006000642000_2026.09.03.749271v1.57","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01670-14"},{"key":"2026091006000642000_2026.09.03.749271v1.58","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.16.7451-7461.2000"},{"key":"2026091006000642000_2026.09.03.749271v1.59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.1989.tb03160.x"},{"key":"2026091006000642000_2026.09.03.749271v1.60","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2003.01620.x"},{"key":"2026091006000642000_2026.09.03.749271v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2010.01.005"},{"key":"2026091006000642000_2026.09.03.749271v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049"},{"key":"2026091006000642000_2026.09.03.749271v1.63","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000490"},{"key":"2026091006000642000_2026.09.03.749271v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.bneo.2026.100200"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.03.749271","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:00:16Z","timestamp":1789045216000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.03.749271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":64,"URL":"https:\/\/doi.org\/10.64898\/2026.09.03.749271","relation":{},"subject":[],"published":{"date-parts":[[2026,9,8]]},"subtype":"preprint"}}