Multifaceted roles for STAT3 in gammaherpesvirus latency revealed through in vivo B cell knockout models

mBio. 2024 Feb 14;15(2):e0299823. doi: 10.1128/mbio.02998-23. Epub 2024 Jan 3.


Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in the B cell-STAT3 knockout mice and more directly evaluate intrinsic roles for STAT3, we generated mixed bone marrow chimeric mice consisting of WT and STAT3 knockout B cells. We discovered a dramatic reduction in latency in STAT3 knockout B cells compared to their WT B cell counterparts in the same lymphoid organ. RNA sequencing of sorted germinal center B cells revealed that MHV68 infection shifts the gene signature toward proliferation and away from type I and type II IFN responses. Loss of STAT3 largely reversed the virus-driven transcriptional shift without impacting the viral gene expression program. STAT3 promoted B cell processes of the germinal center, including IL-21-stimulated downregulation of surface CD23 on B cells infected with MHV68 or EBV. Together, our data provide mechanistic insights into the role of STAT3 as a latency determinant in B cells for oncogenic gammaherpesviruses.IMPORTANCEThere are no directed therapies to the latency program of the human gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus. Activated host factor signal transducer and activator of transcription 3 (STAT3) is a hallmark of cancers caused by these viruses. We applied the murine gammaherpesvirus pathogen system to explore STAT3 function upon primary B cell infection in the host. Since STAT3 deletion in all CD19+ B cells of infected mice led to altered B and T cell responses, we generated chimeric mice with both normal and STAT3-deleted B cells. B cells lacking STAT3 failed to support virus latency compared to normal B cells from the same infected animal. Loss of STAT3 impaired B cell proliferation and differentiation and led to a striking upregulation of interferon-stimulated genes. These findings expand our understanding of STAT3-dependent processes that are key to its function as a pro-viral latency determinant for oncogenic gammaherpesviruses in B cells and may provide novel therapeutic targets.

Keywords: Kaposi sarcoma-associated herpesvirus; STAT transcription factors; gammaherpesvirus; host-pathogen interactions; human herpesviruses; latent infection.

MeSH terms

  • Animals
  • Epstein-Barr Virus Infections*
  • Gammaherpesvirinae* / genetics
  • Herpesviridae Infections*
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / metabolism
  • Herpesvirus 8, Human* / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Rhadinovirus* / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Sarcoma, Kaposi*
  • Virus Latency / genetics


  • STAT3 protein, human
  • STAT3 Transcription Factor
  • Stat3 protein, mouse