Faculty Collaboration Database

T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells. mBio 2022 Aug 30;13(4):e0210722

Date

08/16/2022

Pubmed ID

35968944

Pubmed Central ID

PMC9430880

DOI

10.1128/mbio.02107-22

Scopus ID

2-s2.0-85137124604 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Gammaherpesviruses establish lifelong infections in most vertebrate species, including humans and rodents, and are associated with cancers, including B cell lymphomas. While type I and II interferon (IFN) systems of the host are critical for the control of acute and chronic gammaherpesvirus infection, the cell type-specific role(s) of IFN signaling during infection is poorly understood and is often masked by the profoundly altered viral pathogenesis in the hosts with global IFN deficiencies. STAT1 is a critical effector of all classical IFN responses along with its involvement in other cytokine signaling pathways. In this study, we defined the effect of T cell-specific STAT1 deficiency on the viral and host parameters of infection with murine gammaherpesvirus 68 (MHV68). MHV68 is a natural rodent pathogen that, similar to human gammaherpesviruses, manipulates and usurps B cell differentiation to establish a lifelong latent reservoir in B cells. Specifically, germinal center B cells host the majority of latent MHV68 reservoir in the lymphoid organs, particularly at the peak of viral latency. Unexpectedly, T cell-specific STAT1 expression, while limiting the overall expansion of the germinal center B cell population during chronic infection, rendered these B cells more effective at hosting the latent virus reservoir. Further, T cell-specific STAT1 expression in a wild type host limited circulating levels of IFNγ, with corresponding increases in lytic MHV68 replication and viral reactivation. Thus, our study unveils an unexpected proviral role of T cell-specific STAT1 expression during gammaherpesvirus infection of a natural intact host. IMPORTANCE Interferons (IFNs) represent a major antiviral host network vital to the control of multiple infections, including acute and chronic gammaherpesvirus infections. Ubiquitously expressed STAT1 plays a critical effector role in all classical IFN responses. This study utilized a mouse model of T cell-specific STAT1 deficiency to define cell type-intrinsic role of STAT1 during natural gammaherpesvirus infection. Unexpectedly, T cell-specific loss of STAT1 led to better control of acute and persistent gammaherpesvirus replication and decreased establishment of latent viral reservoir in B cells, revealing a surprisingly diverse proviral role of T cell-intrinsic STAT1.

Author List

Sylvester PA, Jondle CN, Schmalzriedt DL, Dittel BN, Tarakanova VL

Author

Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Gammaherpesvirinae
Herpesviridae Infections
Host-Pathogen Interactions
Humans
Interferons
Mice
Mice, Inbred C57BL
Rhadinovirus
STAT1 Transcription Factor
T-Lymphocytes
Virus Latency