Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are associated with a variety of malignancies, including lymphomas. Interferon Regulatory Factor 7 (IRF-7) is an innate immune transcription factor that restricts acute replication of diverse viruses, including mouse gammaherpesvirus 68 (MHV68). Importantly, very little is known about the role of IRF-7 during chronic virus infections. In this study we demonstrate that IRF-7 attenuates chronic infection by restricting establishment of gammaherpesvirus latency in the peritoneal cavity and, to a lesser extent, viral reactivation in the spleen. Despite the classical role of IRF-7 as a stimulator of type I interferon (IFN) transcription, there were no global effects on the expression of IFN-induced genes (ISGs) in the absence of IRF-7, with only a few ISGs showing attenuated expression in IRF-7 deficient peritoneal cells. Further, IRF-7 expression was dispensable for the induction of virus-specific CD8 T cell response. In contrast, IRF-7 expression restricted latent gammaherpesvirus infection in the peritoneal cavity under conditions when the viral latent reservoir is predominantly hosted by peritoneal B cells. This report is the first demonstration of the antiviral role of IRF-7 during the chronic stage of gammaherpesvirus infection. Importance The innate immune system of the host is critical for the restriction of acute viral infections. In contrast, the role of the innate immune network during chronic herpesvirus infection remains poorly defined. Interferon Regulatory Factor 7 (IRF-7) is a transcription factor with many target genes, including type I interferons (IFNs). In this study we show that the antiviral role of IRF-7 continues into the chronic phase of gammaherpesvirus infection, wherein IRF-7 restricts the establishment of viral latency and viral reactivation. This study is to our knowledge the first to define the role of IRF-7 in chronic virus infection.
Gammaherpesviruses establish lifelong infection and are associated with a variety of cancers, including B cell lymphomas. These viruses manipulate the B cell differentiation process to establish lifelong infection in memory B cells. Specifically, gammaherpesviruses infect naive B cells and promote entry of both infected and uninfected naive B cells into germinal centers, where the virus usurps rapid proliferation of germinal center B cells to exponentially increase its cellular latent reservoir. In addition to facilitating the establishment of latent infection, germinal center B cells are thought to be the target of viral transformation. In this study, we have uncovered a novel proviral role of host interleukin 17A (IL-17A), a well-established antibacterial and antifungal factor. Loss of IL-17A signaling attenuated the establishment of chronic gammaherpesvirus infection and gammaherpesvirus-driven germinal center response in a route of inoculation-dependent manner. Further, IL-17A treatment directly supported gammaherpesvirus reactivation and de novo lytic infection. This study is the first demonstration of a multifaceted proviral role of IL-17 signaling. IMPORTANCE Gammaherpesviruses establish lifelong infections in a majority of humans and are associated with B cell lymphomas. IL-17A is a host cytokine that plays a well-established role in the clearance of bacterial and fungal infections; however, the role of IL-17A in viral infections is poorly understood. In this study, we show that IL-17A signaling promoted the establishment of chronic gammaherpesvirus infection following the mucosal route of infection, viral lytic replication, and reactivation from latency. Thus, our study unveils a novel proviral role of IL-17A signaling in gammaherpesvirus infection.
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 interferon (IFN) beta, a type I IFN. IRF-3 attenuates acute replication of a plethora of viruses, including gammaherpesvirus. Further, IRF-3-driven IFN beta 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. Further, 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. IRF-3 is a critical component of the innate immune response, in part due to its transactivation of IFN beta expression. Similar to 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.
Gammaherpesviruses are ubiquitous pathogens that establish life-long infections in >95% of adults worldwide and are associated with several cancers. We showed that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood. Extracellular cholesterol is carried in the serum by several lipoproteins, including low-density lipoproteins (LDL). The LDL-receptor (LDL-R) mediates the endocytosis of these cholesterol-rich LDL particles into the cell, thereby supplying the cell with cholesterol. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral gene expression in LDL-R -/- primary macrophages. This was not observed in primary fibroblasts, indicating that the antiviral effects of LDL-R are cell type-specific. Increased viral gene expression in LDL-R -/- primary macrophages was due to increased activity of the endogenous cholesterol synthesis pathway. Intriguingly, despite type I interferon-driven increase in LDL-R mRNA levels in infected macrophages, protein levels of LDL-R continually decreased over the single cycle of viral replication. Thus, our study has uncovered an intriguing tug of war between the LDL-R-driven antiviral effect on cholesterol metabolism and the viral targeting of the LDL-R protein. Importance. LDL-R is a cell surface receptor that mediates the endocytosis of cholesterol-rich low density lipoproteins, allowing cells to acquire cholesterol exogenously. Several RNA viruses usurp LDL-R function to facilitate replication; however, the role of LDL-R in DNA virus infection remains unknown. Gammaherpesviruses are double-stranded DNA viruses that are associated with several cancers. Here, we show that LDL-R attenuates gammaherpesvirus replication in primary macrophages by decreasing endogenous cholesterol synthesis activity, a pathway known to support gammaherpesvirus replication. In response, LDL-R protein levels are decreased in infected cells to mitigate the antiviral effects, revealing an intriguing tug-of-war between the virus and the host.
Gammaherpesviruses (GHVs) are ubiquitous pathogens that establish lifelong infections and are associated with a variety of malignancies, including lymphomas. While risk factors for these virus-driven cancers are poorly understood, it is clear that increased reactivation of these viruses from latency contributes to viral oncogenesis. Therefore, it is important to identify host factors that restrict GHV reactivation. Interferon regulatory factor 7(IRF-7) is one of two transcription factors that are primarily responsible for driving type I interferon (IFN) expression and subsequent innate immune responses. Unlike previous studies which have focused on IRF-7 in the context of acute viral infections, we found that GHV reactivation is increased in chronically infected IRF-7−/− mice. Interestingly, the virus-specific T cell response that is typically critical for control of viral reactivation during chronic infection was not decreased in IRF-7−/− mice. However, we observed a decrease in expression of select IFN induced genes (ISGs) in IRF-7−/− GHV-infected mice. Importantly, these differentially affected ISGs have been shown to inhibit GHV replication. Ongoing studies will determine the contribution of IRF- 7 to the expression of IFN, ISGs, and IFN-dependent antiviral activity in the context of chronic GHV infection. Importantly, successful completion of these studies will provide insight into how the host innate immune system controls chronic GHV infections and viral pathogenesis.
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