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See detailHuman/bovine chimeric MxA-like GTPases reveal a contribution of N-terminal domains to the magnitude of anti-influenza A activity
Garigliany, Mutien-Marie ULg; Cornet, Anne ULg; Desmecht, Daniel ULg

in Journal of Interferon & Cytokine Research (2012), 32(7), 326-331

Type I interferons (IFN-) provide powerful and universal innate intracellular defence mechanisms against viruses. Among the antiviral effectors induced by IFN-, Mx proteins of some species appear as ... [more ▼]

Type I interferons (IFN-) provide powerful and universal innate intracellular defence mechanisms against viruses. Among the antiviral effectors induced by IFN-, Mx proteins of some species appear as key components of defence against influenza A viruses. The body of work published to date suggests that to exert anti-influenza activity, an Mx protein must possess a GTP-binding site, structural bases allowing multimerisation, and a specific C-terminal GTPase effector domain (GED). The human MxA and bovine Mx1 proteins both meet these minimal requirements, but the bovine protein is more active against influenza viruses. Here we measured the anti-influenza activity exerted by two human/bovine chimeric Mx proteins. We show that substituting the bovine GED for the human one in human MxA does not affect the magnitude of anti-influenza activity. Strikingly, however, substituting the human GED for the bovine one in bovine Mx1 yields a chimeric protein with much higher anti-influenza activity than the human protein. We conclude, in contradiction to the hypothesis currently in vogue in the literature, that the GED is not the sole determinant controlling the magnitude of the anti-influenza activity exercised by an Mx protein that can bind GTP and multimerise. Our results suggest that one or several motifs that remain to be discovered, located N-terminally with respect to the GED, may interact with a viral component or a cellular factor so as to alter the viral cycle. Identifying, in the N-terminal portion of bovine Mx1, the motif(s) responsible for its higher anti-influenza activity could contribute to the development of new anti-influenza molecules. [less ▲]

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See detailIn vivo modulation of the innate response to pneumovirus by type-I and -III interferon-induced Bos taurus Mx1
Dermine, Martin ULg; Desmecht, Daniel ULg

in Journal of Interferon & Cytokine Research (2012), 32(7), 332-337

The respiratory syncytial virus (RSV) is a major pathogen of the human species. This pneumovirus is a prominent cause of airway morbidity in children and maintains an excessive hospitalization rate ... [more ▼]

The respiratory syncytial virus (RSV) is a major pathogen of the human species. This pneumovirus is a prominent cause of airway morbidity in children and maintains an excessive hospitalization rate despite decades of research. As involvement of a genetic vulnerability is a possibility supported by recent data, we addressed the question of whether the Mx gene products, the typical target of which consists in single-stranded negative-polarity RNA viruses, could alter the course of pneumovirus-associated disease in vivo. Wild-type and Bos taurus Mx1-expressing transgenic FVB/J mice were inoculated with the mouse counterpart and closest phylogenetic relative of RSV, pneumonia virus of mice. Survival data and follow-up of body weight, histological scores, lung virus spread and lung viral load unequivocally showed that the viral infection was severely repressed in Mx-transgenic mice, thus suggesting that pneumoviruses belong to the antiviral spectrum of mammalian Mx GTPases. Elucidating the underlying mechanisms at the molecular level could reveal critical information for the development of new anti-RSV molecules. [less ▲]

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See detailDifferential anti-influenza activity among allelic variants at the Sus scrofa Mx1 locus
Palm, Mélanie; Leroy, Michael; Thomas, Anne et al

in Journal of Interferon & Cytokine Research (2007), 27(2), 147-155

A promising way to oppose infectious challenges would be to improve the resistance of the target species through genetic selection. Theoretically, a candidate gene is available against influenza viruses ... [more ▼]

A promising way to oppose infectious challenges would be to improve the resistance of the target species through genetic selection. Theoretically, a candidate gene is available against influenza viruses since a resistance trait was fortuitously discovered in the A2G mouse strain. This trait was demonstrated to be correlated with the expression of a specific isoform of the type I interferon (IFN)-dependent protein MX, an isoform coded by a specific allele at the mouse Mx1 locus. Two allelic polymorphisms were described recently in the Sus scrofa homologous gene. In this study, the frequencies and distribution of both alleles were evaluated among European domestic pig and wild boar populations by PCR-RFLP, and the anti-influenza activity conferred by both MX1 isoforms was evaluated in vitro using transfection of Vero cells followed by flow cytometric determination of the fraction of influenza virus-infected cells among MX-producing and MX-nonproducing cell populations. A significant difference in the anti-influenza activity brought by the two MX1 isoforms was demonstrated, which suggests that a significant improvement of innate resistance of pigs by genetic selection might be feasible provided the differences found here in vitro are epidemiologically relevant in vivo. [less ▲]

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See detailResistance of paramyxoviridae to type I interferon-induced Bos taurus Mx1 dynamin
Leroy, Michael; Baise, Etienne ULg; Pire, Grégory et al

in Journal of Interferon & Cytokine Research (2005), 25(4), 192-201

Typical targets of type I interferon (IFN)-induced antiviral Mx proteins known to date have been shown to share a common profile: single-stranded negative-sense RNA viruses. Among them, human MxA is known ... [more ▼]

Typical targets of type I interferon (IFN)-induced antiviral Mx proteins known to date have been shown to share a common profile: single-stranded negative-sense RNA viruses. Among them, human MxA is known to interfere with the replication of measles, human, and bovine parainfluenza-3 viruses (BoPi3V), that is, three members of the Paramyxoviridae family. Recently, bovine Mx1 protein (BoMx1) was included in the group of Mx proteins with authenticated antiviral potential, as it dramatically represses the replication of vesicular stomatitis virus (VSV). As replication in bovine cells of Pi3, respiratory syncytial (RS), and Sendai (Se) viruses, all members of the same family, is known to be reduced on IFN-alpha incorporation into the culture medium, it was hypothesized that the BoMx1 pathway possibly was involved, its antiviral spectrum thus probably extending to Paramyxoviridae. In this study, probing of BoMx1-inhibiting effects was carried out by infecting a transgenic Vero cell line that allows tightly regulated conditional expression of BoMx1 after doxycycline treatment with a wide array of Paramyxoviridae. Expressing and nonexpressing cells displayed similar viability, cytopathic effects (CPEs), and amounts of infectious virus yields, whatever the infecting virus or the multiplicity of infection (moi) imposed. It is, therefore, concluded that BoMx1 does not interfere with Paramyxoviridae. [less ▲]

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See detailConditional expression of type I interferon-induced bovine Mx1 GTPase in a stable transgenic vero cell line interferes with replication of vesicular stomatitis virus
Baise, Etienne ULg; Pire, Grégory; Leroy, Michael et al

in Journal of Interferon & Cytokine Research (2004), 24(9), 513-521

In some vertebrate species, type I interferon(IFN)-induced Mx gene expression has been shown to confer resistance to some single-stranded RNA (ssRNA) viruses in vitro. Because the bovine species is ... [more ▼]

In some vertebrate species, type I interferon(IFN)-induced Mx gene expression has been shown to confer resistance to some single-stranded RNA (ssRNA) viruses in vitro. Because the bovine species is subject to an exceptionally wide array of infections caused by such viruses, it is anticipated that an antiviral allele should have been retained by evolution at the bovine Mx locus. The identification of such allele may help in evaluating the real significance of the Mx genotype for disease resistance in vivo, in deciphering host-virus molecular interactions involved, or in improving innate disease resistance of livestock through marker-assisted selection. We validated a double transgenic Vero cell clone in which the bovine Mx1 reference allele is placed under control of the human cytomegalovirus (CMV) enhancer-promoter sequence containing elements from the bacterial tetracycline resistance operon to regulate transcription. In the selected clone, transgene repression was very tight, and derepression by doxycycline led to homogeneous 48-h duration expression of physiologic levels of bovine Mx1. Expression of the transgene caused a dramatic decrease in cytopathic efficiency and a 500-5000-fold yield reduction of the Indiana and New Jersey serotypes of vesicular stomatitis virus (VSV). To our knowledge, the transgenic clone developed here is the first ever reported that allows conditional expression of an Mx protein, thus providing a valuable tool for studying functions of Mx proteins in general and that of bovine Mx1 in particular. This latter may henceforward be included in the group of Mx proteins with authenticated anti-VSV activity, which offers new research avenues into the field of host-virus interactions. [less ▲]

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See detailNF kappa B and interferon regulatory factor 1 physically interact and synergistically induce major histocompatibility class I gene expression.
Drew, P. D.; Franzoso, G.; Becker, K. G. et al

in Journal of Interferon & Cytokine Research (1995), 15(12), 1037-45

Major histocompatibility (MHC) class I gene expression is synergistically induced by the cytokines TNF-alpha and IFN-gamma. However, the mechanism that results in synergistic activation of these genes has ... [more ▼]

Major histocompatibility (MHC) class I gene expression is synergistically induced by the cytokines TNF-alpha and IFN-gamma. However, the mechanism that results in synergistic activation of these genes has remained unclear. We demonstrated here that TNF-alpha induced binding of NF kappa B p50 and p65 to the NF kappa B-like element of the MHC class I promoter termed region I and IFN-gamma induced binding of IRF-1 to the adjacent interferon consensus sequence (ICS). We further demonstrated that NF kappa B and IRF-1 physically interacted with each other and cooperatively induced MHC class I gene expression when cotransfected into CHP-126 neuroblastomas. These results provide a molecular mechanism by which TNF-alpha and IFN-gamma synergistically induce the expression of a variety of genes involved in immune responses, including MHC class I. [less ▲]

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