Interferon Regulatory Factor 3 Supports the Establishment of Chronic Gammaherpesvirus Infection in a Route- and Dose-Dependent Manner. J Virol 2021 Apr 12;95(9)
Date
02/19/2021Pubmed ID
33597211Pubmed Central ID
PMC8104109DOI
10.1128/JVI.02208-20Scopus ID
2-s2.0-85104276444 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are associated with several malignancies, including B cell lymphomas. Uniquely, these viruses manipulate B cell differentiation to establish long-term latency in memory B cells. This study focuses on the interaction between gammaherpesviruses and interferon regulatory factor 3 (IRF-3), a ubiquitously expressed transcription factor with multiple direct target genes, including beta interferon (IFN-β), a type I IFN. IRF-3 attenuates acute replication of a plethora of viruses, including gammaherpesvirus. Furthermore, IRF-3-driven IFN-β expression is antagonized by the conserved gammaherpesvirus protein kinase during lytic virus replication in vitro In this study, we have uncovered an unexpected proviral role of IRF-3 during chronic gammaherpesvirus infection. In contrast to the antiviral activity of IRF-3 during acute infection, IRF-3 facilitated establishment of latent gammaherpesvirus infection in B cells, particularly, germinal center and activated B cells, the cell types critical for both natural infection and viral lymphomagenesis. This proviral role of IRF-3 was further modified by the route of infection and viral dose. Furthermore, using a combination of viral and host genetics, we show that IRF-3 deficiency does not rescue attenuated chronic infection of a protein kinase null gammaherpesvirus mutant, highlighting the multifunctional nature of the conserved gammaherpesvirus protein kinases in vivo In summary, this study unveils an unexpected proviral nature of the classical innate immune factor, IRF-3, during chronic virus infection.IMPORTANCE Interferon regulatory factor 3 (IRF-3) is a critical component of the innate immune response, in part due to its transactivation of beta interferon (IFN-β) expression. Similar to that observed in all acute virus infections examined to date, IRF-3 suppresses lytic viral replication during acute gammaherpesvirus infection. Because gammaherpesviruses establish lifelong infection, this study aimed to define the antiviral activity of IRF-3 during chronic infection. Surprisingly, we found that, in contrast to acute infection, IRF-3 supported the establishment of gammaherpesvirus latency in splenic B cells, revealing an unexpected proviral nature of this classical innate immune host factor.
Author List
Johnson KE, Sylvester PA, Jondle CN, Aurubin CA, Tarakanova VLAuthors
Kaitlin Johnson PhD, BS Research Scientist I in the Obstetrics and Gynecology department at Medical College of WisconsinVera 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
AnimalsB-Lymphocytes
Chronic Disease
Gammaherpesvirinae
Herpesviridae Infections
Host-Pathogen Interactions
Interferon Regulatory Factor-3
Mice
Mice, Inbred C57BL
Mice, Knockout
NIH 3T3 Cells
Spleen
Virus Latency
