{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:13:44Z","timestamp":1791000824328,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            In order to understand and possibly treat B-cell malignancies associated with latent gammaherpesvirus infection, it is vital to understand the factors that control the balance between the two transcriptional states of gammaherpesviruses: latency and lytic replication. We used murine gammaherpesvirus 68 (MHV 68) as a model system to investigate how engagement of endosomal Toll-like receptors (TLRs) impacts reactivation from latency\n            <jats:italic>in vitro<\/jats:italic>\n            and establishment of latent infection\n            <jats:italic>in vivo<\/jats:italic>\n            . We found that treatment with TLR7 ligand R848 or TLR9 ligand CpG oligodeoxynucleotide (ODN) suppresses reactivation of MHV 68\n            <jats:italic>in vitro<\/jats:italic>\n            . These suppressive effects correlated with the ability to activate cellular transcription factor NF-\u03baB. Downregulation of TLR9 by RNA interference\n            <jats:italic>in vitro<\/jats:italic>\n            led to a reduction of nuclear levels of NF-\u03baB p65 and consequently to an increase of spontaneous reactivation in cells latently infected with MHV 68, indicating that the TLR9 pathway suppresses spontaneous reactivation events.\n            <jats:italic>In vivo<\/jats:italic>\n            , sustained stimulation of TLR7 by repeated R848 treatment led to an increased frequency of infected splenocytes compared to mock-treated control results. Frequencies of infected splenic B cells in\n            <jats:italic>tlr7<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            or\n            <jats:italic>tlr9<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice after establishment of latency did not differ from those seen with their wild-type counterparts. Nevertheless, MHV 68-infected B cells from\n            <jats:italic>tlr9<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice showed a higher frequency of reactivation than B cells from wild-type or\n            <jats:italic>tlr7<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice in\n            <jats:italic>ex vivo<\/jats:italic>\n            reactivation assays. Thus, we show a suppressive effect of TLR7 or TLR9 triggering on MHV 68 reactivation that correlates with NF-\u03baB activation and that the mere presence of a functional TLR9 signaling pathway contributes to dampen lytic gammaherpesvirus reactivation in infected cells.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            A hallmark of gammaherpesviruses is their establishment of latency in B cells that is reversible through lytic reactivation. Latency can result in B-cell malignancies. Activation of the innate immune system is thought to contribute to controlling the switch between the transcriptional states of latency and reactivation. Nevertheless, the mechanisms involved are not clear. Here, we show that engagement of Toll-like receptor 7 (TLR7) and TLR9 suppresses reactivation of murine gammaherpesvirus MHV 68\n            <jats:italic>in vitro<\/jats:italic>\n            and that stimulation of TLR7\n            <jats:italic>in vivo<\/jats:italic>\n            increases the frequency of infected cells. TLR7 and TLR9 are innate immunity sensors of nucleic acids localized in endosomes. Additionally, we demonstrate that impairment of TLR9 signaling in latently infected B cells leads to increased reactivation. Thus, activated endosomal TLR7 and TLR9 pathways play an important role in promoting establishment of latent gammaherpesvirus infection. Counteracting signaling of these pathways allows reactivation and could represent treatment targets in gammaherpesvirus-associated malignancies.\n          <\/jats:p>","DOI":"10.1128\/jvi.01486-14","type":"journal-article","created":{"date-parts":[[2014,6,19]],"date-time":"2014-06-19T04:46:54Z","timestamp":1403153214000},"page":"10002-10012","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Activation of NF-\u03baB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation"],"prefix":"10.1128","volume":"88","author":[{"given":"Florian","family":"Haas","sequence":"first","affiliation":[{"name":"Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Murat","sequence":"additional","affiliation":[{"name":"Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Bernasconi","sequence":"additional","affiliation":[{"name":"Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto F.","family":"Speck","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Nadal","sequence":"additional","affiliation":[{"name":"Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1452"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/194232a0"},{"key":"e_1_3_2_4_2","first-page":"19","article-title":"Etiology of Burkitt's lymphoma\u2013an alternative hypothesis to a vectored virus","volume":"42","author":"Burkitt DP","year":"1969","unstructured":"BurkittDP. 1969. 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