title: Murine gammaherpesvirus 68 reactivation from B cells requires IRF4 but not XBP-1.
abstract: Gammaherpesviruses display tropism for B cells and, like all known herpesviruses, exhibit distinct lytic and latent life cycles. One well-established observation among members of the gammaherpesvirus family is the link between viral reactivation from latently infected B cells and plasma cell differentiation. Importantly, a number of studies have identified a potential role for a CREB/ATF family member, X-box binding protein 1 (XBP-1), in trans-activating the immediate early BZLF-1 or BRLF1/gene 50 promoters of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), respectively. XBP-1 is required for the unfolded protein response and has been identified as a critical transcription factor in plasma cells. Here, we demonstrate that XBP-1 is capable of trans-activating the murine gammaherpesvirus 68 (MHV68) RTA promoter in vitro, consistent with previous observations for EBV and KSHV. However, we show that in vivo there does not appear to be a requirement for XBP-1 expression in B cells for virus reactivation. The MHV68 M2 gene product under some experimental conditions plays an important role in virus reactivation from B cells. M2 has been shown to drive B cell differentiation to plasma cells, as well as interleukin-10 (IL-10) production, both of which are dependent on M2 induction of interferon regulatory factor 4 (IRF4) expression. IRF4 is required for plasma cell differentiation, and consistent with a role for plasma cells in MHV68 reactivation from B cells, we show that IRF4 expression in B cells is required for efficient reactivation of MHV68 from splenocytes. Thus, the latter analyses are consistent with previous studies linking plasma cell differentiation to MHV68 reactivation from B cells. The apparent independence of MHV68 reactivation from XBP-1 expression in plasma cells may reflect redundancy among CREB/ATF family members or the involvement of other plasma cell-specific transcription factors. Regardless, these findings underscore the importance of in vivo studies in assessing the relevance of observations made in tissue culture models.
  
  
  OBJECTIVE
  All known herpesviruses establish a chronic infection of their respective host, persisting for the life of the individual. A critical feature of these viruses is their ability to reactivate from a quiescent form of infection (latency) and generate progeny virus. In the case of gammaherpesviruses, which are associated with the development of lymphoproliferative disorders, including lymphomas, reactivation from latently infected B lymphocytes occurs upon terminal differentiation of these cells to plasma cells-the cell type that produces antibodies. A number of studies have linked a plasma cell transcription factor, XBP-1, to the induction of gammaherpesvirus reactivation, and we show here that indeed in tissue culture models this cellular transcription factor can trigger expression of the murine gammaherpesvirus gene involved in driving virus reactivation. However, surprisingly, when we examined the role of XBP-1 in the setting of infection of mice-using mice that lack a functional XBP-1 gene in B cells-we failed to observe a role for XBP-1 in virus reactivation. However, we show that another cellular factor essential for plasma cell differentiation, IRF4, is critical for virus reactivation. Thus, these studies point out the importance of studies in animal models to validate findings from studies carried out in cell lines passaged in vitro.
authors: Microbiology and Molecular Genetics Graduate Program, Emory University, Atlanta, Georgia, USA Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, Georgia, USA.
authors: Caline G
authors: CG
authors: Matar
authors: Microbiology and Molecular Genetics Graduate Program, Emory University, Atlanta, Georgia, USA Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, Georgia, USA.
authors: Udaya Shankari
authors: US
authors: Rangaswamy
authors: Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, USA Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, Georgia, USA.
authors: Brian S
authors: BS
authors: Wakeman
authors: Department of Surgery, Division of Transplantation, Emory School of Medicine, Emory University, Atlanta, Georgia, USA.
authors: Neal
authors: N
authors: Iwakoshi
authors: Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA sspeck@emory.edu.
authors: Samuel H
authors: SH
authors: Speck
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010950:Plasma Cells / Q000378:metabolism / Q000821:virology; D011401:Promoter Regions, Genetic; D000071701:Regulatory Factor X Transcription Factors; D018144:Rhadinovirus / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000821:virology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014764:Viral Proteins; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C577263:M2 protein, murine gammaherpesvirus 68; C000605544:Xbp1 protein, mouse