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Thomas Michiels
De Duve Institute, Université Catholique de Louvain, VIRO B1.74.07, 74, Avenue Hippocrate, 1200 Brussels, Belgium

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Review
Published: 23 June 2021 in Viruses
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Picornaviruses are positive-stranded RNA viruses. Even though replication and translation of their genome take place in the cytoplasm, these viruses evolved different strategies to disturb nucleocytoplasmic trafficking of host proteins and RNA. The major targets of picornavirus are the phenylalanine-glycine (FG)-nucleoporins, which form a mesh in the central channel of the nuclear pore complex through which protein cargos and karyopherins are actively transported in both directions. Interestingly, while enteroviruses use the proteolytic activity of their 2A protein to degrade FG-nucleoporins, cardioviruses act by triggering phosphorylation of these proteins by cellular kinases. By targeting the nuclear pore complex, picornaviruses recruit nuclear proteins to the cytoplasm, where they increase viral genome translation and replication; they affect nuclear translocation of cytoplasmic proteins such as transcription factors that induce innate immune responses and retain host mRNA in the nucleus thereby preventing cell emergency responses and likely making the ribosomal machinery available for translation of viral RNAs.

ACS Style

Belén Lizcano-Perret; Thomas Michiels. Nucleocytoplasmic Trafficking Perturbation Induced by Picornaviruses. Viruses 2021, 13, 1210 .

AMA Style

Belén Lizcano-Perret, Thomas Michiels. Nucleocytoplasmic Trafficking Perturbation Induced by Picornaviruses. Viruses. 2021; 13 (7):1210.

Chicago/Turabian Style

Belén Lizcano-Perret; Thomas Michiels. 2021. "Nucleocytoplasmic Trafficking Perturbation Induced by Picornaviruses." Viruses 13, no. 7: 1210.

Journal article
Published: 28 April 2021 in Scientific Reports
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Eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2), better known as PKR, plays a key role in the response to viral infections and cellular homeostasis by regulating mRNA translation. Upon binding dsRNA, PKR is activated through homodimerization and subsequent autophosphorylation on residues Thr446 and Thr451. In this study, we identified a novel PKR phosphorylation site, Ser6, located 3 amino acids upstream of the first double-stranded RNA binding motif (DRBM1). Another Ser residue occurs in PKR at position 97, the very same position relative to the DRBM2. Ser or Thr residues also occur 3 amino acids upstream DRBMs of other proteins such as ADAR1 or DICER. Phosphoinhibiting mutations (Ser-to-Ala) introduced at Ser6 and Ser97 spontaneously activated PKR. In contrast, phosphomimetic mutations (Ser-to-Asp) inhibited PKR activation following either poly (I:C) transfection or virus infection. These mutations moderately affected dsRNA binding or dimerization, suggesting a model where negative charges occurring at position 6 and 97 tighten the interaction of DRBMs with the kinase domain, thus keeping PKR in an inactive closed conformation even in the presence of dsRNA. This study provides new insights on PKR regulation mechanisms and identifies Ser6 and Ser97 as potential targets to modulate PKR activity for therapeutic purposes.

ACS Style

Teresa Cesaro; Yohei Hayashi; Fabian Borghese; Didier Vertommen; Fanny Wavreil; Thomas Michiels. PKR activity modulation by phosphomimetic mutations of serine residues located three aminoacids upstream of double-stranded RNA binding motifs. Scientific Reports 2021, 11, 1 -16.

AMA Style

Teresa Cesaro, Yohei Hayashi, Fabian Borghese, Didier Vertommen, Fanny Wavreil, Thomas Michiels. PKR activity modulation by phosphomimetic mutations of serine residues located three aminoacids upstream of double-stranded RNA binding motifs. Scientific Reports. 2021; 11 (1):1-16.

Chicago/Turabian Style

Teresa Cesaro; Yohei Hayashi; Fabian Borghese; Didier Vertommen; Fanny Wavreil; Thomas Michiels. 2021. "PKR activity modulation by phosphomimetic mutations of serine residues located three aminoacids upstream of double-stranded RNA binding motifs." Scientific Reports 11, no. 1: 1-16.

Opinion
Published: 28 April 2020 in Environmental Microbiology
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The current SARS‐CoV‐2 pandemic is wreaking havoc throughout the world and has rapidly become a global health emergency. A central question concerning COVID‐19 is why some individuals become sick and others not. Many have pointed already at variation in risk factors between individuals. However, the variable outcome of SARS‐CoV‐2 infections may, at least in part, be due also to differences between the viral subspecies with which individuals are infected. A more pertinent question is how we are to overcome the current pandemic. A vaccine against SARS‐CoV‐2 would offer significant relief, although vaccine developers have warned that design, testing, and production of vaccines may take a year if not longer. Vaccines are based on a handful of different designs (1), but the earliest vaccines were based on live, attenuated virus. As has been the case for other viruses during earlier pandemics, SARS‐CoV‐2 will mutate and may naturally attenuate over time (2). What makes the current pandemic unique is that, thanks to state‐of‐the‐art nucleic acid sequencing technologies, we can follow in detail how SARS‐CoV‐2 evolves while it spreads. We argue that knowledge of naturally emerging attenuated SARS‐CoV‐2 variants across the globe should be of key interest in our fight against the pandemic. This article is protected by copyright. All rights reserved.

ACS Style

Jean Armengaud; Agnès Delaunay‐Moisan; Jean‐Yves Thuret; Eelco Van Anken; Diego Acosta‐Alvear; Tomás Aragón; Carolina Arias; Marc Blondel; Ineke Braakman; Jean‐François Collet; René Courcol; Antoine Danchin; Jean‐François Deleuze; Jean‐Philippe Lavigne Md; Sophie Lucas; Thomas Michiels; Edward R. B. Moore; Jonathon Nixon‐Abell; Ramon Rossello‐Mora; Zheng‐Li Shi; Antonio G. Siccardi; Roberto Sitia; Daniel Tillett; Kenneth N. Timmis; Michel B. Toledano Md; Peter Van Der Sluijs; Elisa Vicenzi. The importance of naturally attenuated SARS‐CoV ‐2 in the fight against COVID ‐19. Environmental Microbiology 2020, 22, 1997 -2000.

AMA Style

Jean Armengaud, Agnès Delaunay‐Moisan, Jean‐Yves Thuret, Eelco Van Anken, Diego Acosta‐Alvear, Tomás Aragón, Carolina Arias, Marc Blondel, Ineke Braakman, Jean‐François Collet, René Courcol, Antoine Danchin, Jean‐François Deleuze, Jean‐Philippe Lavigne Md, Sophie Lucas, Thomas Michiels, Edward R. B. Moore, Jonathon Nixon‐Abell, Ramon Rossello‐Mora, Zheng‐Li Shi, Antonio G. Siccardi, Roberto Sitia, Daniel Tillett, Kenneth N. Timmis, Michel B. Toledano Md, Peter Van Der Sluijs, Elisa Vicenzi. The importance of naturally attenuated SARS‐CoV ‐2 in the fight against COVID ‐19. Environmental Microbiology. 2020; 22 (6):1997-2000.

Chicago/Turabian Style

Jean Armengaud; Agnès Delaunay‐Moisan; Jean‐Yves Thuret; Eelco Van Anken; Diego Acosta‐Alvear; Tomás Aragón; Carolina Arias; Marc Blondel; Ineke Braakman; Jean‐François Collet; René Courcol; Antoine Danchin; Jean‐François Deleuze; Jean‐Philippe Lavigne Md; Sophie Lucas; Thomas Michiels; Edward R. B. Moore; Jonathon Nixon‐Abell; Ramon Rossello‐Mora; Zheng‐Li Shi; Antonio G. Siccardi; Roberto Sitia; Daniel Tillett; Kenneth N. Timmis; Michel B. Toledano Md; Peter Van Der Sluijs; Elisa Vicenzi. 2020. "The importance of naturally attenuated SARS‐CoV ‐2 in the fight against COVID ‐19." Environmental Microbiology 22, no. 6: 1997-2000.

Journal article
Published: 01 October 2019 in Journal of Virology
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The leader (L) protein encoded by cardioviruses is a very short multifunctional protein that contributes to evasion of the host innate immune response. This protein notably prevents the formation of stress granules in infected cells. Using Theiler’s virus as a model, we show that L proteins can act at two levels in the stress response pathway leading to stress granule formation, the most striking one being the inhibition of eucaryotic translation initiation factor 2 alpha kinase 2 (PKR) activation. Interestingly, the leader protein appears to inhibit PKR via a novel mechanism by rendering this kinase unable to detect double-stranded RNA, its typical activator. Unlike other viral proteins, such as influenza virus NS1, the leader protein appears to interact with neither PKR nor double-stranded RNA, suggesting that it acts indirectly to trigger the inhibition of the kinase.

ACS Style

Fabian Borghese; Frédéric Sorgeloos; Teresa Cesaro; Thomas Michiels. The Leader Protein of Theiler's Virus Prevents the Activation of PKR. Journal of Virology 2019, 93, 1 .

AMA Style

Fabian Borghese, Frédéric Sorgeloos, Teresa Cesaro, Thomas Michiels. The Leader Protein of Theiler's Virus Prevents the Activation of PKR. Journal of Virology. 2019; 93 (19):1.

Chicago/Turabian Style

Fabian Borghese; Frédéric Sorgeloos; Teresa Cesaro; Thomas Michiels. 2019. "The Leader Protein of Theiler's Virus Prevents the Activation of PKR." Journal of Virology 93, no. 19: 1.

Journal article
Published: 16 August 2019 in 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.

ACS Style

Sophie Jacobs; Caroline Zeippen; Fanny Wavreil; Laurent Gillet; Thomas Michiels. IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa. Viruses 2019, 11, 757 .

AMA Style

Sophie Jacobs, Caroline Zeippen, Fanny Wavreil, Laurent Gillet, Thomas Michiels. IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa. Viruses. 2019; 11 (8):757.

Chicago/Turabian Style

Sophie Jacobs; Caroline Zeippen; Fanny Wavreil; Laurent Gillet; Thomas Michiels. 2019. "IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa." Viruses 11, no. 8: 757.

Journal article
Published: 01 November 2018 in Journal of Interferon & Cytokine Research
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The type III interferon (IFN-λ) family includes 4 IFN-λ subtypes in man. In the mouse, only the genes coding for IFN-λ2 and -λ3 are present. Unlike mouse and human type I IFNs (IFN-α/β), which exhibit strong species specificity, type III IFNs were reported to act in a cross-specific manner. We reexamined the cross-specificity and observed that mouse and human IFN-λ exhibit some species specificity, although much less than type I IFNs. Mouse IFN-λ3 displayed clear species specificity, being 25-fold less active in human cells than the closely related mouse IFN-λ2. This specificity likely depends on amino acids in α helices A and F that diverged from other IFN-λ sequences. Human IFN-λ4, in contrast, retained high activity in mouse cells. We next developed a firefly luciferase-based reporter cell line, named Fawa-λ-luc, to detect IFN-λ in biological fluids with high specificity and sensitivity. Fawa-λ-luc cells, derived from mouse epithelial cells that are responsive to IFN-λ, were made nonresponsive to type I IFNs by inactivation of the Ifnar2 gene and strongly responsive to IFN-λ by overexpression of the mouse IFNLR1. This bioassay was as sensitive as a commercially available enzyme-linked immunosorbent assay in detecting mouse IFN-λ in cell culture supernatant, as well as in serum and bronchoalveolar lavage samples of virus-infected mice. The assay also enabled the sensitive detection of human IFN-λ activity, including that of the divergent IFN-λ4 with a bias, however, due to variable activity of IFN-λ subtypes.

ACS Style

Sophie Jacobs; Fanny Wavreil; Bert Schepens; Hans Henrik Gad; Rune Hartmann; Joana Rocha-Pereira; Johan Neyts; Xavier Saelens; Thomas Michiels. Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ. Journal of Interferon & Cytokine Research 2018, 38, 469 -479.

AMA Style

Sophie Jacobs, Fanny Wavreil, Bert Schepens, Hans Henrik Gad, Rune Hartmann, Joana Rocha-Pereira, Johan Neyts, Xavier Saelens, Thomas Michiels. Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ. Journal of Interferon & Cytokine Research. 2018; 38 (11):469-479.

Chicago/Turabian Style

Sophie Jacobs; Fanny Wavreil; Bert Schepens; Hans Henrik Gad; Rune Hartmann; Joana Rocha-Pereira; Johan Neyts; Xavier Saelens; Thomas Michiels. 2018. "Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ." Journal of Interferon & Cytokine Research 38, no. 11: 469-479.

Review article
Published: 12 October 2018 in Frontiers in Microbiology
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Cardioviruses are members of the Picornaviridae family and infect a variety of mammals, from mice to humans. Replication of cardioviruses produces double stranded RNA that is detected by helicases in the RIG-I-like receptor family and leads to a signaling cascade to produce type I interferon. Like other viruses within Picornaviridae, however, cardioviruses have evolved several mechanisms to inhibit interferon production. In this review, we summarize recent findings that have uncovered several proteins enabling efficient detection of cardiovirus dsRNA and discuss which cell types may be most important for interferon production in vivo. Additionally, we describe how cardiovirus proteins L, 3C and L∗ disrupt interferon production and antagonize the antiviral activity of interferon effector molecules.

ACS Style

Eric C. Freundt; Melissa Drappier; Thomas Michiels. Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling. Frontiers in Microbiology 2018, 9, 1 .

AMA Style

Eric C. Freundt, Melissa Drappier, Thomas Michiels. Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling. Frontiers in Microbiology. 2018; 9 ():1.

Chicago/Turabian Style

Eric C. Freundt; Melissa Drappier; Thomas Michiels. 2018. "Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling." Frontiers in Microbiology 9, no. : 1.

Book chapter
Published: 01 June 2018 in Encyclopedia of Signaling Molecules
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ACS Style

Melissa Drappier; Thomas Michiels. Ribonuclease L (RNase L). Encyclopedia of Signaling Molecules 2018, 4709 -4717.

AMA Style

Melissa Drappier, Thomas Michiels. Ribonuclease L (RNase L). Encyclopedia of Signaling Molecules. 2018; ():4709-4717.

Chicago/Turabian Style

Melissa Drappier; Thomas Michiels. 2018. "Ribonuclease L (RNase L)." Encyclopedia of Signaling Molecules , no. : 4709-4717.

Research article
Published: 13 April 2018 in PLOS Pathogens
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The OAS/RNase L pathway is one of the best-characterized effector pathways of the IFN antiviral response. It inhibits the replication of many viruses and ultimately promotes apoptosis of infected cells, contributing to the control of virus spread. However, viruses have evolved a range of escape strategies that act against different steps in the pathway. Here we unraveled a novel escape strategy involving Theiler’s murine encephalomyelitis virus (TMEV) L* protein. Previously we found that L* was the first viral protein binding directly RNase L. Our current data show that L* binds the ankyrin repeats R1 and R2 of RNase L and inhibits 2’-5’ oligoadenylates (2-5A) binding to RNase L. Thereby, L* prevents dimerization and oligomerization of RNase L in response to 2-5A. Using chimeric mouse hepatitis virus (MHV) expressing TMEV L*, we showed that L* efficiently inhibits RNase L in vivo. Interestingly, those data show that L* can functionally substitute for the MHV-encoded phosphodiesterase ns2, which acts upstream of L* in the OAS/RNase L pathway, by degrading 2-5A. Oligoadenylate synthetases (OAS) are a family of enzymes that produce 2’-5’ oligoadenylates (2-5A) from ATP. OAS accumulate as inactive enzymes in cells that have been exposed to interferon. When infection of these cells occurs, double-stranded RNA produced during virus replication activates OAS, which produce 2-5A. 2-5A act as second messengers. They bind a cellular endonuclease called RNase L, thereby triggering the dimerization and the activation of this RNase. Active RNase L degrades cellular and viral RNA molecules, ultimately killing the infected cell, thus preventing virus spread. Viruses have developed diverse mechanisms to escape RNase L activity. We report that Theiler’s murine encephalomyelitis virus, a virus that produces persistent infections of the central nervous system, evolved a novel mechanism to escape the OAS/RNase L pathway. The L* protein produced by this virus binds RNase L very close to the pocket known to sense 2-5A and thereby prevents 2-5A from activating RNase L. This mechanism contrasts with that used by Influenza (flu) virus, which sequesters double-stranded RNA and thereby also inhibits alternative antiviral pathways. We further showed that the RNase L antagonist activity of L* is effective in vivo and that L* can substitute for 2-5A degrading enzymes produced by coronaviruses.

ACS Style

Melissa Drappier; Babal Kant Jha; Sasha Stone; Ruth Elliott; Rong Zhang; Didier Vertommen; Susan R. Weiss; Robert H. Silverman; Thomas Michiels. A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L. PLOS Pathogens 2018, 14, e1006989 .

AMA Style

Melissa Drappier, Babal Kant Jha, Sasha Stone, Ruth Elliott, Rong Zhang, Didier Vertommen, Susan R. Weiss, Robert H. Silverman, Thomas Michiels. A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L. PLOS Pathogens. 2018; 14 (4):e1006989.

Chicago/Turabian Style

Melissa Drappier; Babal Kant Jha; Sasha Stone; Ruth Elliott; Rong Zhang; Didier Vertommen; Susan R. Weiss; Robert H. Silverman; Thomas Michiels. 2018. "A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L." PLOS Pathogens 14, no. 4: e1006989.

Journal article
Published: 01 January 2018 in Antiviral Research
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Human noroviruses are highly efficient in person to person transmission thus associated with explosive outbreaks of acute gastroenteritis. Outbreak control is limited to disinfection and isolation measures. Strategies to control the spread of noroviruses should be developed and models to study norovirus transmission will greatly facilitate this. Here, a mouse-to-mouse transmission model, in which mice develop acute murine norovirus (MNV)-induced diarrhea, was used to explore the role of interferon lambda (IFN-λ) in the control of a norovirus infection. Sentinel AG129 mice [deficient in IFN-α/β and IFN-γ receptors] that were co-housed with MNV-infected mice shedding high amounts of virus in their stool, developed a MNV-infection with associated diarrhea. Inoculation of such sentinel mice with an IFN-λ expression plasmid resulted in the production of circulating IFN-λ and upregulation of the expression of IFN-stimulated genes (ISGs) of the gut. Injection of the IFN-λ-expressing plasmid to sentinels prevents MNV-induced disease upon exposure to MNV-infected mice, as well as MNV replication in the small intestine, the associated signs of inflammation and the mounting of a specific IgG-based immune response. This demonstrates that IFN-λ can alone mediate protection against transmission of norovirus. The development of a simple delivery method for IFN-λ could be explored as a strategy to control norovirus outbreaks and protect vulnerable populations such as the elderly and immunocompromised.

ACS Style

Joana Rocha-Pereira; Sophie Jacobs; Sam Noppen; Eric Verbeken; Thomas Michiels; Johan Neyts. Interferon lambda (IFN-λ) efficiently blocks norovirus transmission in a mouse model. Antiviral Research 2018, 149, 7 -15.

AMA Style

Joana Rocha-Pereira, Sophie Jacobs, Sam Noppen, Eric Verbeken, Thomas Michiels, Johan Neyts. Interferon lambda (IFN-λ) efficiently blocks norovirus transmission in a mouse model. Antiviral Research. 2018; 149 ():7-15.

Chicago/Turabian Style

Joana Rocha-Pereira; Sophie Jacobs; Sam Noppen; Eric Verbeken; Thomas Michiels; Johan Neyts. 2018. "Interferon lambda (IFN-λ) efficiently blocks norovirus transmission in a mouse model." Antiviral Research 149, no. : 7-15.

Journal article
Published: 15 July 2017 in Journal of Virology
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Vilyuisk human encephalitis virus (VHEV) is a picornavirus related to Theiler's murine encephalomyelitis virus (TMEV). VHEV was isolated from human material passaged in mice. Whether this VHEV is of human or mouse origin is therefore unclear. We took advantage of the species-specific activity of the nonstructural L* protein of theiloviruses to track the origin of TMEV isolates. TMEV L* inhibits RNase L, the effector enzyme of the interferon pathway. By using coimmunoprecipitation and functional RNase L assays, the species specificity of RNase L antagonism was tested for L* from mouse (DA) and rat (RTV-1) TMEV strains as well as for VHEV. Coimmunoprecipitation and functional assay data confirmed the species specificity of L* activity and showed that L* from rat strain RTV-1 inhibited rat but not mouse or human RNase L. Next, we showed that the VHEV L* protein was phylogenetically related to L* of mouse viruses and that it failed to inhibit human RNase L but readily antagonized mouse RNase L, unambiguously showing the mouse origin of VHEV. IMPORTANCE Defining the natural host of a virus can be a thorny issue, especially when the virus was isolated only once or when the isolation story is complex. The species Theilovirus includes Theiler's murine encephalomyelitis virus (TMEV), infecting mice and rats, and Saffold virus (SAFV), infecting humans. One TMEV strain, Vilyuisk human encephalitis virus (VHEV), however, was isolated from mice that were inoculated with cerebrospinal fluid of a patient presenting with chronic encephalitis. It is therefore unclear whether VHEV was derived from the human sample or from the inoculated mouse. The L* protein encoded by TMEV inhibits RNase L, a cellular enzyme involved in innate immunity, in a species-specific manner. Using binding and functional assays, we show that this species specificity even allows discrimination between TMEV strains of mouse and of rat origins. The VHEV L* protein clearly inhibited mouse but not human RNase L, indicating that this virus originates from mice.

ACS Style

Melissa Drappier; Fred R. Opperdoes; Thomas Michiels. Nonstructural Protein L* Species Specificity Supports a Mouse Origin for Vilyuisk Human Encephalitis Virus. Journal of Virology 2017, 91, e00573-17 .

AMA Style

Melissa Drappier, Fred R. Opperdoes, Thomas Michiels. Nonstructural Protein L* Species Specificity Supports a Mouse Origin for Vilyuisk Human Encephalitis Virus. Journal of Virology. 2017; 91 (14):e00573-17.

Chicago/Turabian Style

Melissa Drappier; Fred R. Opperdoes; Thomas Michiels. 2017. "Nonstructural Protein L* Species Specificity Supports a Mouse Origin for Vilyuisk Human Encephalitis Virus." Journal of Virology 91, no. 14: e00573-17.

Journal article
Published: 30 March 2017 in Journal of Neurochemistry
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A critical role has been assigned to protein kinase C (PKC)ε in the control of intracellular calcium oscillations triggered upon activation of type 5 metabotropic glutamate receptor (mGluR5) in cultured astrocytes. Nevertheless, the physiological significance of this particular signalling profile in the response of astrocytes to glutamate remains largely unknown. Considering that kinases are frequently involved in the regulation of G protein-coupled receptors, we have examined a putative link between the nature of the calcium signals and the response regulation upon repeated exposures of astrocytes to the agonist (S)-3,5-dihydroxyphenylglycine. We show that upon repeated mGluR5 activations, a robust desensitization was observed in astrocytes grown in culture conditions favouring the peak-plateau-type response. At variance, in cell cultures where calcium oscillations were predominating, the response was fully preserved even during repeated challenges with the agonist. Pharmacological inhibition of PKCε or genetic suppression of this isoform using shRNA was found to convert an oscillatory calcium profile to a sustained calcium mobilization and this latter profile was subject to desensitization upon repetitive mGluR5 activation. Our results suggest a yet undocumented scheme in which the activity of PKCε contributes to preserve the receptor sensitivity upon repeated or sustained activations. Cover Image for this issue: doi: 10.1111/jnc.13797.

ACS Style

Maxime Vergouts; Pierre J. Doyen; Michael Peeters; Remi Opsomer; Thomas Michiels; Emmanuel Hermans. PKC epsilon-dependent calcium oscillations associated with metabotropic glutamate receptor 5 prevent agonist-mediated receptor desensitization in astrocytes. Journal of Neurochemistry 2017, 141, 387 -399.

AMA Style

Maxime Vergouts, Pierre J. Doyen, Michael Peeters, Remi Opsomer, Thomas Michiels, Emmanuel Hermans. PKC epsilon-dependent calcium oscillations associated with metabotropic glutamate receptor 5 prevent agonist-mediated receptor desensitization in astrocytes. Journal of Neurochemistry. 2017; 141 (3):387-399.

Chicago/Turabian Style

Maxime Vergouts; Pierre J. Doyen; Michael Peeters; Remi Opsomer; Thomas Michiels; Emmanuel Hermans. 2017. "PKC epsilon-dependent calcium oscillations associated with metabotropic glutamate receptor 5 prevent agonist-mediated receptor desensitization in astrocytes." Journal of Neurochemistry 141, no. 3: 387-399.

Short article
Published: 01 February 2017 in Cell Host & Microbe
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Summary Both endotherms and ectotherms (e.g., fish) increase their body temperature to limit pathogen infection. Ectotherms do so by moving to warmer places, hence the term "behavioral fever." We studied the manifestation of behavioral fever in the common carp infected by cyprinid herpesvirus 3, a native carp pathogen. Carp maintained at 24°C died from the infection, whereas those housed in multi-chamber tanks encompassing a 24°C–32°C gradient migrated transiently to the warmest compartment and survived as a consequence. Behavioral fever manifested only at advanced stages of infection. Consistent with this, expression of CyHV-3 ORF12, encoding a soluble decoy receptor for TNF-α, delayed the manifestation of behavioral fever and promoted CyHV-3 replication in the context of a temperature gradient. Injection of anti-TNF-α neutralizing antibodies suppressed behavioral fever, and decreased fish survival in response to infection. This study provides a unique example of how viruses have evolved to alter host behavior to increase fitness.

ACS Style

Krzysztof Rakus; Maygane Ronsmans; Maria Forlenza; Maxime Boutier; M. Carla Piazzon; Joanna Jazowiecka-Rakus; Derek Gatherer; Alekos Athanasiadis; Frédéric Farnir; Andrew J. Davison; Pierre Boudinot; Thomas Michiels; Geert Wiegertjes; Alain Vanderplasschen. Conserved Fever Pathways across Vertebrates: A Herpesvirus Expressed Decoy TNF-α Receptor Delays Behavioral Fever in Fish. Cell Host & Microbe 2017, 21, 244 -253.

AMA Style

Krzysztof Rakus, Maygane Ronsmans, Maria Forlenza, Maxime Boutier, M. Carla Piazzon, Joanna Jazowiecka-Rakus, Derek Gatherer, Alekos Athanasiadis, Frédéric Farnir, Andrew J. Davison, Pierre Boudinot, Thomas Michiels, Geert Wiegertjes, Alain Vanderplasschen. Conserved Fever Pathways across Vertebrates: A Herpesvirus Expressed Decoy TNF-α Receptor Delays Behavioral Fever in Fish. Cell Host & Microbe. 2017; 21 (2):244-253.

Chicago/Turabian Style

Krzysztof Rakus; Maygane Ronsmans; Maria Forlenza; Maxime Boutier; M. Carla Piazzon; Joanna Jazowiecka-Rakus; Derek Gatherer; Alekos Athanasiadis; Frédéric Farnir; Andrew J. Davison; Pierre Boudinot; Thomas Michiels; Geert Wiegertjes; Alain Vanderplasschen. 2017. "Conserved Fever Pathways across Vertebrates: A Herpesvirus Expressed Decoy TNF-α Receptor Delays Behavioral Fever in Fish." Cell Host & Microbe 21, no. 2: 244-253.

Book chapter
Published: 21 December 2016 in Encyclopedia of Signaling Molecules
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SynonymsPRCA1; RNS4Historical BackgroundIn early stages of viral infection, the innate immune response and particularly the interferon response play a critical role in restricting viral replication and propagation, awaiting the establishment of the adaptive immune response. One of the best-described IFN-dependent antiviral responses is the OAS/RNase L pathway. This two-component system is controlled by type I and type III interferons (IFN). Back in the 1970s, the groups of I. Kerr and P. Lengyel discovered a cellular endoribonuclease (RNase) activity that was increased by IFN and depended on the presence of double-stranded RNA (dsRNA) (Brown et al. 1976; Kerr et al. 1977). Further, a correlation was found between this RNase activity and the synthesis of unusual 2′-5′ oligoadenylates (2-5A) (Fig. 1) by a family of enzymes called oligoadenylate synthetases (OAS) [(Baglioni et al. 1978), reviewed by (Hovanessian and Justesen 2007)].Fig. 1Structure of 2′-5′ oligoadenylates (2-5A). 2-5A are ...

ACS Style

Melissa Drappier; Thomas Michiels. Ribonuclease L (RNase L). Encyclopedia of Signaling Molecules 2016, 1 -9.

AMA Style

Melissa Drappier, Thomas Michiels. Ribonuclease L (RNase L). Encyclopedia of Signaling Molecules. 2016; ():1-9.

Chicago/Turabian Style

Melissa Drappier; Thomas Michiels. 2016. "Ribonuclease L (RNase L)." Encyclopedia of Signaling Molecules , no. : 1-9.

Journal article
Published: 01 June 2016 in Journal of General Virology
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Saffold virus (SAFV) is a highly seroprevalent human Cardiovirus discovered recently. No clear association between SAFV infection and human disease has been established. Rare infection cases, however, correlated with neurological symptoms. To gain insight into the pathogenesis potential of the virus, we performed experimental mouse infection with SAFV strains of genotypes 2 and 3 (SAFV-2 and SAFV-3). After intraperitoneal infection, both strains exhibited a typical Cardiovirus tropism. Viral load was most prominent in the pancreas. Heart, spleen, brain and spinal cord were also infected. In interferon receptor deficient (IFNAR-KO) mice, SAFV-3 caused a severe encephalitis. The virus was detected by immunohistochemistry in many parts of the brain and spinal cord, both in neurons and astrocytes but astrocyte infection was more extensive. In vitro, SAFV-3 also infected astrocytes better than neurons in mixed primary cultures. Astrocytes were, however, very efficiently protected by IFN-α/β treatment.

ACS Style

Frederic Sorgeloos; Cécile Lardinois; Sophie Jacobs; Frank J. M. Van Kuppeveld; Bernd Kaspers; Thomas Michiels. Neurotropism of Saffold virus in a mouse model. Journal of General Virology 2016, 97, 1350 -1355.

AMA Style

Frederic Sorgeloos, Cécile Lardinois, Sophie Jacobs, Frank J. M. Van Kuppeveld, Bernd Kaspers, Thomas Michiels. Neurotropism of Saffold virus in a mouse model. Journal of General Virology. 2016; 97 (6):1350-1355.

Chicago/Turabian Style

Frederic Sorgeloos; Cécile Lardinois; Sophie Jacobs; Frank J. M. Van Kuppeveld; Bernd Kaspers; Thomas Michiels. 2016. "Neurotropism of Saffold virus in a mouse model." Journal of General Virology 97, no. 6: 1350-1355.

Hepatology
Published: 22 March 2016 in Gut
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Objective The hepatitis E virus (HEV) is responsible for approximately 20 million infections per year worldwide. Although most infected people can spontaneously clear an HEV infection, immune-compromised individuals may evolve towards chronicity. Chronic HEV infection can be cured using ribavirin, but viral isolates with low ribavirin sensitivity have recently been identified. Although some HEV isolates can be cultured in vitro, in vivo studies are essentially limited to primates and pigs. Since the use of these animals is hampered by financial, practical and/or ethical concerns, we evaluated if human liver chimeric mice could serve as an alternative. Design Humanised mice were inoculated with different HEV-containing preparations. Results Chronic HEV infection was observed after intrasplenic injection of cell culture-derived HEV, a filtered chimpanzee stool suspension and a patient-derived stool suspension. The viral load was significantly higher in the stool compared with the plasma. Overall, the viral titre in genotype 3-infected mice was lower than that in genotype 1-infected mice. Analysis of liver tissue of infected mice showed the presence of viral RNA and protein, and alterations in host gene expression. Intrasplenic injection of HEV-positive patient plasma and oral inoculation of filtered stool suspensions did not result in robust infection. Finally, we validated our model for the evaluation of novel antiviral compounds against HEV using ribavirin. Conclusions Human liver chimeric mice can be infected with HEV of different genotypes. This small animal model will be a valuable tool for the in vivo study of HEV infection and the evaluation of novel antiviral molecules.

ACS Style

Ibrahim M Sayed; Lieven Verhoye; Laurence Cocquerel; Florence Abravanel; Lander Foquet; Claire Montpellier; Yannick Debing; Ali Farhoudi; Czeslaw Wychowski; Jean Dubuisson; Geert Leroux-Roels; Johan Neyts; Jacques Izopet; Thomas Michiels; Philip Meuleman. Study of hepatitis E virus infection of genotype 1 and 3 in mice with humanised liver. Gut 2016, 66, 920 -929.

AMA Style

Ibrahim M Sayed, Lieven Verhoye, Laurence Cocquerel, Florence Abravanel, Lander Foquet, Claire Montpellier, Yannick Debing, Ali Farhoudi, Czeslaw Wychowski, Jean Dubuisson, Geert Leroux-Roels, Johan Neyts, Jacques Izopet, Thomas Michiels, Philip Meuleman. Study of hepatitis E virus infection of genotype 1 and 3 in mice with humanised liver. Gut. 2016; 66 (5):920-929.

Chicago/Turabian Style

Ibrahim M Sayed; Lieven Verhoye; Laurence Cocquerel; Florence Abravanel; Lander Foquet; Claire Montpellier; Yannick Debing; Ali Farhoudi; Czeslaw Wychowski; Jean Dubuisson; Geert Leroux-Roels; Johan Neyts; Jacques Izopet; Thomas Michiels; Philip Meuleman. 2016. "Study of hepatitis E virus infection of genotype 1 and 3 in mice with humanised liver." Gut 66, no. 5: 920-929.

Journal article
Published: 10 March 2016 in Viruses
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Picornavirus’ genomic RNA is a positive-stranded RNA sequence that also serves as a template for translation and replication. Cellular microRNAs were reported to interfere to different extents with the replication of specific picornaviruses, mostly acting as inhibitors. However, owing to the high error rate of their RNA-dependent RNA-polymerases, picornavirus quasi-species are expected to evolve rapidly in order to lose any detrimental microRNA target sequence. We examined the genome of Theiler’s murine encephalomyelitis virus (TMEV) for the presence of under-represented microRNA target sequences that could have been selected against during virus evolution. However, little evidence for such sequences was found in the genome of TMEV and introduction of the most under-represented microRNA target (miR-770-3p) in TMEV did not significantly affect viral replication in cells expressing this microRNA. To test the global impact of cellular microRNAs on viral replication, we designed a strategy based on short-term Dicer inactivation in mouse embryonic fibroblasts. Short-term Dicer inactivation led to a >10-fold decrease in microRNA abundance and strongly increased replication of Vesicular stomatitis virus (VSV), which was used as a microRNA-sensitive control virus. In contrast, Dicer inactivation did not increase TMEV replication. In conclusion, cellular microRNAs appear to exert little influence on Theiler’s virus fitness.

ACS Style

Aurélie De Cock; Thomas Michiels. Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler’s Virus Replication. Viruses 2016, 8, 75 .

AMA Style

Aurélie De Cock, Thomas Michiels. Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler’s Virus Replication. Viruses. 2016; 8 (3):75.

Chicago/Turabian Style

Aurélie De Cock; Thomas Michiels. 2016. "Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler’s Virus Replication." Viruses 8, no. 3: 75.

Journal article
Published: 15 February 2016 in Journal of Virology
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Interferon beta (IFN-β) is a key component of cellular innate immunity in mammals, and it constitutes the first line of defense during viral infection. Studies with cultured cells previously showed that almost all nucleated cells are able to produce IFN-β to various extents, but information about the in vivo sources of IFN-β remains incomplete. By applying immunohistochemistry and employing conditional-reporter mice that express firefly luciferase under the control of the IFN-β promoter in either all or only distinct cell types, we found that astrocytes are the main producers of IFN-β after infection of the brain with diverse neurotropic viruses, including rabies virus, Theiler's murine encephalomyelitis virus, and vesicular stomatitis virus. Analysis of a panel of knockout mouse strains revealed that sensing of viral components via both RIG-I-like helicases and Toll-like receptors contributes to IFN induction in the infected brain. A genetic approach to permanently mark rabies virus-infected cells in the brain showed that a substantial number of astrocytes became labeled and, therefore, must have been infected by the virus at least transiently. Thus, our results strongly indicate that abortive viral infection of astrocytes can trigger pattern recognition receptor signaling events which result in secretion of IFN-β that confers antiviral protection. IMPORTANCE Previous work indicated that astrocytes are the main producers of IFN after viral infection of the central nervous system (CNS), but it remained unclear how astrocytes might sense those viruses which preferentially replicate in neurons. We have now shown that virus sensing by both RIG-I-like helicases and Toll-like receptors is involved. Our results further demonstrate that astrocytes get infected in a nonproductive manner under these conditions, indicating that abortive infection of astrocytes plays a previously unappreciated role in the innate antiviral defenses of the CNS.

ACS Style

Cathleen Pfefferkorn; Carsten Kallfass; Stefan Lienenklaus; Julia Spanier; Ulrich Kalinke; Martina Rieder; Karl-Klaus Conzelmann; Thomas Michiels; Peter Staeheli. Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain. Journal of Virology 2016, 90, 2031 -2038.

AMA Style

Cathleen Pfefferkorn, Carsten Kallfass, Stefan Lienenklaus, Julia Spanier, Ulrich Kalinke, Martina Rieder, Karl-Klaus Conzelmann, Thomas Michiels, Peter Staeheli. Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain. Journal of Virology. 2016; 90 (4):2031-2038.

Chicago/Turabian Style

Cathleen Pfefferkorn; Carsten Kallfass; Stefan Lienenklaus; Julia Spanier; Ulrich Kalinke; Martina Rieder; Karl-Klaus Conzelmann; Thomas Michiels; Peter Staeheli. 2016. "Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain." Journal of Virology 90, no. 4: 2031-2038.

Journal article
Published: 01 November 2015 in Cytokine
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Human noroviruses are the leading cause of foodborne illness. Without available vaccines or antiviral drugs, new strategies are needed for outbreak control. We recently established a transmission model using the genogroup V murine norovirus (MNV) in which we demonstrated that MNV is efficiently transmitted from infected (seeder) animals to non-infected (sentinel) IFNAR-IFNGR double KO mice [1]. Interferon lambda (IFN-λ)λ) has been shown to act primarily on epithelial cells in vivo. Hence, IFN-λ has a determining role in the control of viral infections targeting the intestinal epithelia, such as rotavirus and reovirus. Treatment with exogenous IFN-λ has also been shown to cure an ongoing persistent norovirus infection [2]. Here, we studied the impact of IFN-λ on mouse-to-mouse virus transmission, using the norovirus model. Sentinel mice were electroinjected in the tibialis muscle with a plasmid expressing IFN-λ3 (or an empty vector); sentinel mice were then caged together with infected seeder mice and monitored daily. While untreated sentinels developed norovirus-induced diarrhea, shed MNV from day 6 post-infection (pi) onwards and had to be euthanized between day 7 and 11 pi, those electroporated with IFN-λ did not develop disease, shed no MNV and remained healthy. Fluorescent in situ hybridization detected MNV in the lamina propria of seeder and untreated sentinels, while in IFN-λ electroporated mice, a strong Oasl2 signal in the epithelia was observed and no virus was detected. Hence, IFN-λ can completely prevent mouse-to-mouse transmission of norovirus.

ACS Style

Joana Rocha-Pereira; Sophie Jacobs; Thomas Michiels; Johan Neyts. ID: 146. Cytokine 2015, 76, 94 .

AMA Style

Joana Rocha-Pereira, Sophie Jacobs, Thomas Michiels, Johan Neyts. ID: 146. Cytokine. 2015; 76 (1):94.

Chicago/Turabian Style

Joana Rocha-Pereira; Sophie Jacobs; Thomas Michiels; Johan Neyts. 2015. "ID: 146." Cytokine 76, no. 1: 94.

Conference abstract
Published: 11 September 2015 in Cytokine
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Interferon-β (IFN-β) is a key component of cellular innate immunity in mammals, and it constitutes the first line of defence during viral infection. In vitro studies showed that almost all nucleated cells are able to produce IFN-β to various extents, but information about the in vivo source of IFN-β remains incomplete. Since prominent IFN producer cells such as plasmacytoid dendritic cells are usually absent from the brain parenchyma, other cell types must be responsible for the synthesis of IFN after virus infection of this organ. By applying immunohistochemistry and employing conditional reporter mice that express firefly luciferase under control of the IFN-β promoter in either all or only distinct cell types, we found that astrocytes are the main producers of IFN-β after infection of the brain with diverse neurotropic viruses, including rabies virus, Theiler’s murine encephalomyelitis virus and vesicular stomatitis virus. This finding was surprising given the fact that neurons are the principal targets of all these viruses. Analysis of a panel of knockout mouse strains revealed that sensing of viral components via both RIG-I-like helicases and Toll-like receptors contributes to IFN induction in the virus-infected brain. When using an in vivo approach to permanently mark infected cells, we observed that a substantial number of astrocytes must have transiently encountered virus during early stages of the infection. Thus, our data strongly indicate that abortive viral infection of astrocytes triggers pattern-recognition receptor signalling, which results in secretion of IFN-β.

ACS Style

Cathleen Pfefferkorn; Carsten Kallfass; Stefan Lienenklaus; Julia Spanier; Ulrich Kalinke; Martina Rieder; Karl-Klaus Conzelmann; Thomas Michiels; Peter Staeheli. ID: 158. Cytokine 2015, 76, 95 .

AMA Style

Cathleen Pfefferkorn, Carsten Kallfass, Stefan Lienenklaus, Julia Spanier, Ulrich Kalinke, Martina Rieder, Karl-Klaus Conzelmann, Thomas Michiels, Peter Staeheli. ID: 158. Cytokine. 2015; 76 (1):95.

Chicago/Turabian Style

Cathleen Pfefferkorn; Carsten Kallfass; Stefan Lienenklaus; Julia Spanier; Ulrich Kalinke; Martina Rieder; Karl-Klaus Conzelmann; Thomas Michiels; Peter Staeheli. 2015. "ID: 158." Cytokine 76, no. 1: 95.