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Type I and II interferons (IFNs) are critical for the control of acute and chronic gammaherpesvirus infection. However, the cell type-specific role of IFN signaling during natural infection is poorly defined and is masked by the altered viral pathogenesis observed in hosts with global IFN deficiencies. STAT1 is a constitutively expressed transcription factor that is critical for the effector function of type I and II IFNs. In this study, we defined the impact of B cell-specific STAT1 expression on gammaherpesvirus infection using murine gammaherpesvirus 68 (MHV68). While the acute stage of MHV68 infection was not affected, we found opposite, anatomic site-dependent effects of B cell-intrinsic STAT1 expression during chronic infection. Consistent with the antiviral role of STAT1, B cell-specific STAT1 expression attenuated the latent viral reservoir in peritoneal B cells of chronically infected mice. In contrast, STAT1 expression in splenic B cells supported the establishment of the latent MHV68 reservoir in germinal center B cells, revealing an unexpected proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection. These STAT1-dependent MHV68 chronic infection phenotypes were fully recapitulated in the peritoneal cavity but not the spleen of mice with B cell-specific deficiency of type I IFN receptor. In summary, our study uncovers the intriguing combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.<\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Interferons (IFNs) execute broadly antiviral roles during acute and chronic viral infections. The constitutively expressed transcription factor STAT1 is a critical downstream effector of IFN signaling. Our studies demonstrate that B cell-intrinsic STAT1 expression has opposing and anatomic site-dependent roles during chronic gammaherpesvirus infection. Specifically, B cell-intrinsic STAT1 expression restricted gammaherpesvirus latent reservoir in the peritoneal cavity, consistent with the classical antiviral role of STAT1. In contrast, decreased STAT1 expression in splenic B cells led to the attenuated establishment of gammaherpesvirus latency and decreased latent infection of germinal center B cells, highlighting a novel proviral role of B cell-intrinsic STAT1 expression during chronic infection with a B cell-tropic gammaherpesvirus. Interestingly, B cell-specific type I IFN receptor deficiency primarily recapitulated the antiviral role of B cell-intrinsic STAT1 expression, suggesting the compensatory function of B cell-intrinsic type II IFN signaling or an IFN-independent proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01598-24","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:00:55Z","timestamp":1729688455000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression defines parameters of chronic gammaherpesvirus infection"],"prefix":"10.1128","volume":"15","author":[{"given":"Erika R.","family":"Johansen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon L.","family":"Schmalzriedt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilela","family":"Avila","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Sylvester","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cade R.","family":"Rahlf","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, 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