STAT1 and herpesviruses: Making lemonade from lemons.

Signal transducer and activator of transcription 1 (STAT1) is engaged downstream of interferon and other cytokine receptors and has traditionally been defined as an antiviral effector of the host. Consistent with the antiviral role, genetic deficiency of STAT1 leads to increased replication of diverse viruses and severe disease that can lead to host's mortality, including in rare human cases of STAT1 insufficiency. Surprisingly, excessive STAT1 activation recently identified in patients with heterozygous gain-of-function STAT1 mutations and subsequently modeled in laboratory mice, also leads to poor control of select virus infections, including herpesviruses.

Role of Interferon Regulatory Factor 1 in acute and chronic virus infections.

Decades of research have defined the function of interferon regulatory factors (IRFs) in the antiviral immune response. Interferon regulatory factor-1 (IRF-1) is the founding member of the IRF family, with recognized antiviral effects across diverse virus infections. While most antiviral activities of IRF-1 were defined in vitro, fewer studies examined the role of IRF-1 during viral infection of an intact host.

Combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression defines parameters of chronic gammaherpesvirus infection.

Gammaherpesviruses are species-specific, ubiquitous pathogens that establish lifelong infection in their hosts and are associated with cancers, including B cell lymphomas. Type I and II interferons (IFNs) are critical for the control of acute and chronic gammaherpesvirus infection. However, the cell type-specific role of IFN signaling during natural infection is poorly defined and is masked by the altered viral pathogenesis observed in hosts with global IFN deficiencies.

Nontypeable Haemophilus influenzae challenge during gammaherpesvirus infection enhances viral reactivation and latency.

Gammaherpesviruses are ubiquitous, lifelong pathogens associated with multiple cancers that infect over 95% of the adult population. Increases in viral reactivation, due to stress and other unknown factors impacting the immune response, frequently precedes lymphomagenesis. One potential stressor that could promote viral reactivation and increase viral latency would be the myriad of infections from bacterial and viral pathogens that we experience throughout our lives.

Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.

Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells.

T cell-extrinsic IL-1 signaling controls long-term gammaherpesvirus infection by suppressing viral reactivation.

Gammaherpesviruses establish life-long infection in over 95% of adults and are associated with several cancers, including B cell lymphomas. Using the murine gammaherpesvirus 68 (MHV68) animal model, we previously showed a pro-viral role of Interleukin-1 (IL-1) signaling that supported viral reactivation during the establishment of chronic infection. Unexpectedly, in this study we found that the proviral effects of IL-1 signaling originally observed during the establishment of chronic gammaherpesvirus infection convert to antiviral effects during the long-term stage of infection.

The Antagonism between the Murine Gammaherpesvirus Protein Kinase and Global Interferon Regulatory Factor 1 Expression Shapes the Establishment of Chronic Infection.

Gammaherpesviruses infect most vertebrate species and are associated with B cell lymphomas. Manipulation of B cell differentiation is critical for natural infection and lymphomagenesis driven by gammaherpesviruses. Specifically, human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) drive differentiation of infected naive B cells into the germinal center to achieve exponential increase in the latent viral reservoir during the establishment of chronic infection.

T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells.

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.

T Cell-Intrinsic Interleukin 17 Receptor A Signaling Supports the Establishment of Chronic Murine Gammaherpesvirus 68 Infection.

Gammaherpesviruses, such as human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), are species-specific, ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a unique and robust polyclonal germinal center response to establish a long-term latent reservoir in memory B cells. The robust polyclonal germinal center response driven by gammaherpesvirus infection increases the risk for B cell transformation.

Mouse Homologue of Human HLA-DO Does Not Preempt Autoimmunity but Controls Murine Gammaherpesvirus MHV68.

H2-O (human HLA-DO) is a relatively conserved nonclassical MHC class II (MHCII)-like molecule. H2-O interaction with human HLA-DM edits the repertoire of peptides presented to TCRs by MHCII. It was long hypothesized that human HLA-DM inhibition by H2-O provides protection from autoimmunity by preventing binding of the high-affinity self-peptides to MHCII.

[Oxidation-reduction potential of tissues of the oral mucosal wound surface under the photodynamic action].

Unlabelled: The of the study was to examine the condition of the pro-antioxidant balance of the homogenates of tissues of the oral mucosal wound surface in vivo experiment under the photodynamic action of combined two-wave radiation to eliminate its damaging effect on the structures of cell membranes.

Materials And Methods: On the mucous membrane of the cheeks of sexually mature female autocrats of Wistar rats (=72) experimental models of wound surfaces with a diameter of 3 mm were formed. The animals were divided into groups: control (=36) and experimental (=36).

T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4 T Cell Populations That Support Chronic Gammaherpesvirus Infection.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation.

MyD88 is an essential regulator of NK cell-mediated clearance of MCMV infection.

The signaling adapter MyD88 is critical for immune cell activation in response to viral or bacterial pathogens via several TLRs, IL-1βR and IL-18R. However, the essential role of MyD88 during activations mediated by germline-encoded NK cell receptors (NKRs), such as Ly49H or NKG2D, has yet to be investigated. To define the NK cell-intrinsic function of MyD88, we generated a novel NK cell conditional knockout mouse for MyD88 (Myd88Ncr1).

Conserved Gammaherpesvirus Protein Kinase Counters the Antiviral Effects of Myeloid Cell-Specific STAT1 Expression To Promote the Establishment of Splenic B Cell Latency.

Gammaherpesviruses establish lifelong infections and are associated with B cell lymphomas. Murine gammaherpesvirus 68 (MHV68) infects epithelial and myeloid cells during acute infection, with subsequent passage of the virus to B cells, where physiological B cell differentiation is usurped to ensure the establishment of a chronic latent reservoir. Interferons (IFNs) represent a major antiviral defense system that engages the transcriptional factor STAT1 to attenuate diverse acute and chronic viral infections, including those of gammaherpesviruses.

Low-Density Lipoprotein Receptor Suppresses the Endogenous Cholesterol Synthesis Pathway To Oppose Gammaherpesvirus Replication in Primary Macrophages.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in >95% of adults worldwide and are associated with several cancers. We have shown that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood.

Gammaherpesvirus Usurps Host IL-17 Signaling To Support the Establishment of Chronic 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.

Interferon Regulatory Factor 3 Supports the Establishment of Chronic Gammaherpesvirus Infection in a Route- and Dose-Dependent Manner.

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.

STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer.

Background & Aims: Pancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/β-receptor (IFNAR) signaling in systemic antitumor immune responses.

Interferon Regulatory Factor 7 Attenuates Chronic Gammaherpesvirus Infection.

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 murine gammaherpesvirus 68 (MHV68). Importantly, very little is known about the role of IRF-7 during chronic virus infections.

Innate immunity and alpha/gammaherpesviruses: first impressions last a lifetime.

Innate immune system is considered the first line of defense during viral invasion, with the wealth of the literature demonstrating innate immune control of diverse viruses during acute infection. What is far less clear is the role of innate immune system during chronic virus infections. This short review focuses on alphaherpesviruses and gammaherpesviruses, two highly prevalent herpesvirus subfamilies that, following a brief, once in a lifetime period of acute lytic infection, establish life-long latent infection that is characterized by sporadic reactivation in an immunocompetent host.