Melanoma Differentiation-Associated Gene 5 Is Critical for Protection against Theiler's Virus-Induced Demyelinating Disease

Section: Discussionmentioning

confidence: 55%

“…First, IFN production in astrocytes seems to be due to cytoplasmic detection of viral RNA via RLRs. These pathways were previously shown to contribute to recognition of rabies virus and TMEV strain GDVII (25,26). Second, IFN production via MyD88/Trif-dependent TLR signaling seems to play a role.…”

Section: Discussionmentioning

confidence: 85%

Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain

Pfefferkorn

Kallfass

Lienenklaus

et al. 2016

“…Bar graphs represent means Ϯ standard errors of the means. *, P Ͻ 0.05; **, P Ͻ 0.01. data, enhanced viral replication of SeV, RV, murine norovirus 1 (MNV-1), and Theiler's virus has been reported in MDA5 Ϫ/Ϫ mice (38,39,52,55).…”

Section: Discussionmentioning

confidence: 97%

Critical Role of MDA5 in the Interferon Response Induced by Human Metapneumovirus Infection in Dendritic Cells and In Vivo

Baños-Lara

Ghosh

Guerrero-Plata

2013

Human metapneumovirus (hMPV) is a respiratory paramyxovirus of global clinical relevance. Despite the substantial knowledge generated during the last 10 years about hMPV infection, information regarding the activation of the immune response against this virus remains largely unknown. In this study, we demonstrated that the helicase melanoma differentiation-associated gene 5 (MDA5) is essential to induce the interferon response after hMPV infection in human and mouse dendritic cells as well as in an experimental mouse model of infection. Our findings in vitro and in vivo showed that MDA5 is required for the expression and activation of interferon (IFN) regulatory factors (IRFs). hMPV infection induces activation of IRF-3, and it regulates the expression of IRF-7. However, both IRF-3 and IRF-7 are critical for the production of type I and type III IFNs. In addition, our in vivo studies in hMPV-infected mice indicated that MDA5 alters viral clearance, enhances disease severity and pulmonary inflammation, and regulates the production of cytokines and chemokines in response to hMPV. These findings are relevant for a better understanding of the pathogenesis of hMPV infection.

“…Because previous studies showed antiviral effects of the TLR and RLR signaling pathways in resident cells of the CNS (12,(35)(36)(37), we hypothesized that part of the enhanced WNV infection phenotype in Irf5 Ϫ/Ϫ mice could be explained by an IRF5-dependent restriction of replication in resident neuronal cells or micro- Ϫ/Ϫ mice from at least three independent experiments. The difference was statistically different (P Ͻ 0.0001), as judged by the log-rank test.…”

Section: At Day 4 After Infection 4 Of 11 Irf5mentioning

confidence: 99%

Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

Thackray

Shrestha

Richner

et al. 2014

Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2 mu/mu ) in several Irf5 ؊/؊ mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5 ؊/؊ ؋ Dock2 wt/wt mice (here called Irf5 ؊/؊ mice) and independently generated CMV-Cre Irf5 fl/fl mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5؊/؊ and CMV-Cre Irf5 fl/fl mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5 ؊/؊ mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5 ؊/؊ mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. A canonical model for type I IFN production after virus infection is a two-step positive feedback loop that is regulated by Interferon regulatory factor 3 (IRF3) and IRF7 (1). Detection of viral nucleic acids by Toll-like receptors (TLRs), RIG-I-like (RLRs) receptors, or DNA sensors induces nuclear localization of IRF3, which in concert with NF-B and ATF-2/c-Jun stimulates transcription, synthesis, and secretion of IFN-␤ by infected cells. Extracellular interferon beta (IFN-␤) binds to the type I IFN receptor (IFNAR) and triggers activation of the JAK-STAT signaling pathway and induction of IFN-stimulated genes (ISGs) (2), which inhibit viral entry, translation, replication, and assembly through a variety of independent mechanisms (reviewed in reference 3). While IRF3 is constitutively expressed in many tissues, IRF7 is an ISG required for the expression of most IFN-␣ subtypes and is thus a key mediator of the type I IFN amplification loop (1, 4).Noncanonical signaling pathways also induce type I IFN responses. Even with genetic ablation of IRF3 and IRF7 (Irf3 Ϫ/Ϫ ϫ Irf7 Ϫ/Ϫ double-knockout [DKO] cells or mice), type I IFN was produced after infection with West Nile virus (WNV), dengue virus, murine norovirus, or murine cytomegalovirus, albeit at reduced levels compared to wild-type ...