The IFN regulatory factor 7‐dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infection

Steinberg, Christian; Eisenächer, Katharina; Groß, Olaf; Reindl, Wolfgang; Schmitz, Frank; Ruland, Jürgen; Krug, Anne

doi:10.1002/eji.200838814

Cited by 39 publications

(42 citation statements)

References 43 publications

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“…This result contrasts with previous studies with IRF -7 Ϫ/Ϫ mice, in which the amplification loop was abolished and IFN-␣ response in circulation after viral infection was blunted (16,34,64). However, similarly elevated systemic type I IFN levels were observed after WNV infection in TLR-7 Ϫ/Ϫ , MyD88 Ϫ/Ϫ , IPS-1 Ϫ/Ϫ , and IRF-3 Ϫ/Ϫ mice (14,65,66,70).…”

Section: Discussioncontrasting

confidence: 98%

Beta Interferon Controls West Nile Virus Infection and Pathogenesis in Mice

Lazear

Pinto

Vogt

et al. 2011

J Virol

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Section: Discussioncontrasting

confidence: 98%

Beta Interferon Controls West Nile Virus Infection and Pathogenesis in Mice

Lazear

Pinto

Vogt

et al. 2011

J Virol

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“…The systemic expression of IFNA genes was completely dependent on Irf7 after murine cytomegalovirus (MCMV) infection in mice but independent of Irf3, whereas IFNB production was not affected in single knockout (KO) or double KO (DKO) Irf3/Irf7 mice. However, single KO or DKO Irf3/Irf7 mice were only modestly more susceptible than wild-type (WT) mice to MCMV infections [15] . Mice lacking Irf3 and Irf7 as single KO or DKO still produced reduced levels of Ifnb1 in myeloid dendritic cells after West Nile virus infection, but only additional deletion of Irf5 resulted in increased susceptibility to West Nile virus and murine norovirus in triple KO mice [16] .…”

Section: Introductionmentioning

confidence: 99%

Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Hatesuer

Hoang

Riese³

et al. 2016

J Innate Immun

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The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3^-/-, Irf7^-/-, and Irf3^-/-Irf7^-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

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“…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 (WT) cells and mice (5)(6)(7)(8).…”

mentioning

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

J Virol

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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 ...

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The IFN regulatory factor 7‐dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infection

Cited by 39 publications

References 43 publications

Beta Interferon Controls West Nile Virus Infection and Pathogenesis in Mice

Beta Interferon Controls West Nile Virus Infection and Pathogenesis in Mice

Deletion of <b><i>Irf3</i></b> and <b><i>Irf7</i></b> Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

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

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