Blockade of Chronic Type I Interferon Signaling to Control Persistent LCMV Infection
Department of Microbiology, Immunology and Molecular Genetics and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Science
(Impact Factor: 33.61).
04/2013; 340(6129):202-7. DOI: 10.1126/science.1235208
Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.
Available from: Andreas Bergthaler
- "Insights into this innate immunity-driven immunopathology provide a paradigm for infection-associated tissue damage by uncovering the redox system as a crucial effector downstream of the IFN-driven innate immune response. This establishes a molecular connection between cellular homeostasis, metabolism , and tissue damage in the context of viral infection and adds to the ongoing efforts to understand the pleiotropic antiviral and immunomodulatory effects of IFN-I (McNab et al., 2015; Schoggins et al., 2011; Teijaro et al., 2013; Wilson et al., 2013). "
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ABSTRACT: Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.
Available from: Vishal Khairnar
- "On the one hand, IFN-I is clearly antiviral, and it can influence the very early viral replication that can affect the course of persistent infection . On the other hand, it induces programmed death ligand 1 (PD-L1) and interleukin IL-10 and thereby drives CD8 þ Tcell exhaustion  . Therefore limited production of IFN-I in the presence of highly activated CD8 þ T cells results in severe immunopathology . "
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ABSTRACT: The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system.
Available from: Dan Longo
- "Some studies suggest that local cytokine exposure during infection might play a polarizing role on naive CD4 + T cells toward a certain T helper (Th) cell subset upon subsequent coinfection with a secondary pathogen (Perona-Wright et al., 2010). Other studies suggest that elevated cytokine concentrations might play a role in propagating the exhaustion that occurs during chronic infections (Teijaro et al., 2013; Wilson et al., 2013). Immune stimulatory therapies are being increasingly successfully applied as cancer treatments. "
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ABSTRACT: Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions.
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