Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ

Jacobs, Sophie; Wavreil, Fanny; Schepens, Bert; Gad, Hans Henrik; Hartmann, Rune; Rocha‐Pereira, Joana; Neyts, Johan; Saelens, Xavier; Michiels, Thomas

doi:10.1089/jir.2018.0066

Cited by 11 publications

(16 citation statements)

References 36 publications

(46 reference statements)

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“…These cells were infected with Theiler's murine encephalomyelitis virus (TMEV), a positive strand RNA virus belonging to the Picornaviridae family. We used a genetically modified virus, which has a deleted L protein, rendering the virus highly susceptible to the antiviral effects of PKR and expressing the fluorescent protein Cherry, used as a reporter to quantify virus replication (36). Following virus adsorption for 1 h, cells were either treated with vehicle only or treated with 50 μM Sephin1.…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, HEK293T cells were infected with JEV at a MOI of 0.01 for 48 h and JEV RNAs in cell supernatants were quantified by real-time RT-PCR as described in Yang et al (35). Theiler's murine encephalomyelitis virus (TMEV) genetically modified to express a mutant L protein and the fluorescent protein Cherry (36) was used to infect MEF WT and MEF S51A. Cellular viability was measured with Vita-Blue Cell Viability Reagent (Biomake) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

et al. 2019

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The guanabenz derivative Sephin1 has recently been proposed to increase the levels of translation initiation factor 2 (eIF2α) phosphorylation by inhibiting dephosphorylation by the protein phosphatase 1—GADD34 (PPP1R15A) complex. As phosphorylation of eIF2α by protein kinase R (PKR) is a prominent cellular antiviral pathway, we evaluated the consequences of Sephin1 treatment on virus replication. Our results provide evidence that Sephin1 downregulates replication of human respiratory syncytial virus, measles virus, human adenovirus 5 virus, human enterovirus D68, human cytomegalovirus, and rabbit myxoma virus. However, Sephin1 proved to be inactive against influenza virus, as well as against Japanese encephalitis virus. Sephin1 increased the levels of phosphorylated eIF2α in cells exposed to a PKR agonist. By contrast, in virus-infected cells, the levels of phosphorylated eIF2α did not always correlate with the inhibition of virus replication by Sephin1. This work identifies Sephin1 as an antiviral molecule in cell culture against RNA, as well as DNA viruses belonging to phylogenetically distant families.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

et al. 2019

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“…BALB/c female mice were housed at the University of Liège, Department of Infectious Diseases, FARAH. B6.A2G-Mx1-IFNAR1 −/− female mice were kindly provided by Peter Stäheli (Freiburg University, Freiburg, Germany) [43].…”

Section: Methodsmentioning

confidence: 99%

“…Plasmids pSJ1 and pSJ7 are pcDNA3 derivatives (Invitrogen, Thermo Fisher Scientific) carrying ORFs of mouse IFN-λ2 and IFN-λ3 [43]. The lentiviral vector pSJ12, used for expression of mouse IFNLR1, was obtained by cloning the Ifnlr1 ORF between the Bam HI and Xba I sites of pTM945, a lentiviral vector allowing the coexpression of the cloned gene and of mCherry [54].…”

Section: Methodsmentioning

confidence: 99%

IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa

Jacobs

Zeippen

Wavreil

et al. 2019

Viruses

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Murid herpesvirus-4 (MuHV-4), a natural gammaherpesvirus of rodents, can infect the mouse through the nasal mucosa, where it targets sustentacular cells and olfactory neurons in the olfactory epithelium before it propagates to myeloid cells and then to B cells in lymphoid tissues. After establishment of latency in B cells, viral reactivation occurs in the genital tract in 80% of female mice, which can lead to spontaneous sexual transmission to co-housed males. Interferon-lambda (IFN-λ) is a key player of the innate immune response at mucosal surfaces and is believed to limit the transmission of numerous viruses by acting on epithelial cells. We used in vivo plasmid-mediated IFN-λ expression to assess whether IFN-λ could prophylactically limit MuHV-4 infection in the olfactory and vaginal mucosae. In vitro, IFN-λ decreased MuHV-4 infection in cells that overexpressed IFN-λ receptor 1 (IFNLR1). In vivo, prophylactic IFN-λ expression decreased infection of the olfactory epithelium but did not prevent virus propagation to downstream organs, such as the spleen where the virus establishes latency. In the olfactory epithelium, sustentacular cells readily responded to IFN-λ. In contrast, olfactory neurons did not respond to IFN-λ, thus, likely allowing viral entry. In the female genital tract, columnar epithelial cells strongly responded to IFN-λ, as did most vaginal epithelial cells, although with some variation from mouse to mouse. IFN-λ expression, however, failed to prevent virus reactivation in the vaginal mucosa. In conclusion, IFN-λ decreased MuHV-4 replication in the upper respiratory epithelium, likely by protecting the sustentacular epithelial cells, but it did not protect olfactory neurons and failed to block virus reactivation in the genital mucosa.

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“…Murine Ifnl2 and Ifnl3 are highly homologous to their human orthologs, and the murine Ifnlr1 receptor subunit likewise shares a high degree of sequence identity with the human subunit (17). As a result of these similarities, both human and murine IFN-s display some cross-species reactivity (18).…”

mentioning

confidence: 99%

Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

Peterson

Kennedy

Brigleb

et al. 2019

J Virol

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Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2−/− Ifnl3−/− mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1−/− mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore genocopy Ifnlr1−/− mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens. IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1. Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.

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Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ

Cited by 11 publications

References 36 publications

Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa

Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

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