Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8+ T Cell Immune Responses against West Nile Virus Infection

Gammaherpesviruses are ubiquitous pathogens that are associated with the development of B cell lymphomas. Gammaherpesviruses employ multiple mechanisms to transiently stimulate a broad, polyclonal germinal center reaction, an inherently mutagenic stage of B cell differentiation that is thought to be the primary target of malignant transformation in virus-driven lymphomagenesis. We found that this gammaherpesvirus-driven germinal center expansion was exaggerated and lost its transient nature in the absence of interferon-regulatory factor 1 (IRF-1), a transcription factor with antiviral and tumor suppressor functions. Uncontrolled and persistent expansion of germinal center B cells led to pathological changes in the spleens of chronically infected IRF-1-deficient animals. Additionally, we found decreased IRF-1 expression in cases of human posttransplant lymphoproliferative disorder, a malignant condition associated with gammaherpesvirus infection. The results of our study define an unappreciated role for IRF-1 in B cell biology and provide insight into the potential mechanism of gammaherpesvirus-driven lymphomagenesis. IMPORTANCE Gammaherpesviruses establish lifelong infection in most adults and are associated with B cell lymphomas. While the infection is asymptomatic in many hosts, it is critical to identify individuals who may be at an increased risk of virus-induced cancer. Such identification is currently impossible Interferon-regulatory factor 1 (IRF-1) is a conserved transcription factor that restricts the replication of diverse RNA and DNA viruses in vitro via a poorly understood mechanism (1, 2). Additionally, IRF-1 suppresses replication and restricts the tropism of West Nile virus (WNV) (3), vesicular stomatitis virus (VSV) (4), and murine norovirus (5) during the acute phase of infection in vivo. However, there is a paucity of studies defining the role of IRF-1 during chronic virus infection. Such a role undoubtedly exists, as distinct IRF-1 polymorphisms are associated with either susceptibility to chronic hepatitis B and C virus infection (6) or resistance to HIV-1 (7). Additionally, IRF-1 is a tumor suppressor, as evidenced by the synergy between IRF-1 insufficiency and oncogene deregulation in animal models (8) and decreased IRF-1 expression in several human cancers (9). Importantly, this tumor suppressor nature of IRF-1 may be of particular relevance in the context of chronic infection with cancer-associated viruses.Our study focuses on the interaction between IRF-1 and gammaherpesviruses, ubiquitous pathogens that establish lifelong infection in a majority of the human population and are associated with the development of B cell lymphomas (10). In spite of the widespread nature of gammaherpesvirus infection, the host risk factors that predispose individuals toward gammaherpesvirus-driven lymphomagenesis are still poorly understood. Gammaherpesviruses establish long-term latency in memory B cells. Accordingly, these viruses employ both viral and host mechanisms to stimulate a germinal cent...

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“…3B). Further, an exaggerated germinal center response was not reported in IRF-1 Ϫ/Ϫ mice infected with WNV, VSV, or murine norovirus (3)(4)(5).…”

Section: Discussionmentioning

confidence: 89%

“…IRF-1 restricts the tropism of WNV and VSV for the central nervous system during the acute phase of infection (3,4). Thus, the tropism of MHV68 was assessed in BL6 and IRF-1 Ϫ/Ϫ mouse spleens.…”

Section: Irf-1 Deficiency Does Not Alter Mhv68 Tropism For Splenic B mentioning

confidence: 99%

Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus

Mboko

Olteanu

Ray

et al. 2016

J Virol

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“…While initially IRF-1 was thought to induce type I interferon (IFN) expression (15), it soon became clear that IRF-1 functions downstream of IFN expression during viral infection in vitro and in vivo (16)(17)(18)(19). We demonstrated (19) that one mechanism by which IRF-1 restricts gammaherpesvirus replication in primary macrophage cultures is via transcriptional induction of cholesterol-25-hydroxylase (CH25H), an enzyme whose product displays broad antiviral activities (20,21).…”

mentioning

confidence: 93%

“…Of those tested, IRF-1 restricted replication of West Nile virus (WNV) (16), vesicular stomatitis virus (VSV) (22), and murine norovirus (MNV) (18) during acute infection. Interestingly, IRF-1 contributes to IFN-␥-mediated control of MNV replication in primary macrophages in vitro and during acute infection in vivo, especially under conditions when type I IFN signaling is inhibited (18).…”

mentioning

confidence: 99%

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

Mboko

Rekow

Ledwith

et al. 2017

J Virol

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Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in Ͼ95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection.IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.KEYWORDS IRF-1, acute infection, gammaherpesvirus, interferon, viral replication G ammaherpesviruses are ubiquitous pathogens that establish lifelong infection in a majority of the adult population and are associated with cancer (1-3). Similar to replication of other viruses, replication of both human (Epstein-Barr virus [EBV] and Kaposi's sarcoma-associated herpesvirus [KSHV]) and murine (mouse gammaherpesvirus 68[MHV68]) gammaherpesviruses is suppressed by type I and type II interferons (IFNs), two partially overlapping yet distinct host networks that are critical for the control of gammaherpesvirus infection (4-10). In the case of MHV68, both acute and chronic MHV68 infection is attenuated by type I and type II IFNs (4,6,11,12). While the antiviral role of IFNs in the context of gammaherpesvirus infection, including in vivo, is firmly established, the mechanism by which this restriction is imposed and the molecular players involved in this response are still being defined.Interferon regulatory factor 1 (IRF-1) is a broadly antiviral transcription factor that restricts replication of diverse RNA and DNA viruses in cell culture via a poorly understood mechanism (13, 14). While initially IRF-1 was thought to induce type I interferon (IFN) expression (15)

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“…On the other hand, NF-kb induced IRF-1 activation (figure :9) [73]. This transcription factor is an immunomodulatory factor, it works downstream of the pathogen recognition receptor signaling [74]. Furthermore, activation of PI3K is due to the inhibition of the production of IL-12 (figure :10) [75], [76].…”

Section: B Cytoscapementioning

confidence: 99%

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2017

RJLBPCS

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ABSTRACT:One of the many challenges of bioinformatics, now a day; is the integration of biological data.The establishment of large quantities of data concerning the differentially expressed genes during infection with an intracellular pathogen requires the implementation of integration strategies to gather all the data and therefore a better understanding of the functioning of the Intracellular infection. This work aims to exploit the bioinformatics approach, to provide a new interpretation of the data available in the literature as well as databases on the effect of intracellular infection, cases of the Leishmania parasite, on the host. A total of 30 genes expressed differently from a Leishmania parasite infection were used for functional analysis using the bioinformatics tool. The latter provides rapid assessment of signaling and metabolic pathways, molecular networks and biological processes that are more significantly disrupted in a data set of interest. Bioinformatics analysis revealed that apoptosis, cytokine production, and signaling were altered following infection with the Leishmania parasite. The genes of IL-10, IL-4, IL-6, SOD1, EIF2AK2, NF-kB and PI3K/akt were most activated after Infection by the Leishmania parasite. The results suggest that the Leishmania parasite reverses immune and inflammatory responses, meaning the ability to induce programmed cell death and microbicidal functions of macrophages such as inhibition of nitric oxide (NO), And the functions of the inducible cytokines of macrophages. Analyzing and interpreting data using the bioinformatics approach helps to unlock knowledge buried in experimental data by quickly identifying links, mechanisms, functions and main pathways to move beyond Statistical analysis to new biological analyzes.

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Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8+ T Cell Immune Responses against West Nile Virus Infection

Cited by 82 publications

References 80 publications

Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus

Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

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