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PubMed1998

Mx1-based resistance to thogoto virus in A2G mice is bypassed in tick-mediated virus delivery.

The interferon-induced mouse Mx1 protein has intrinsic antiviral activity against orthomyxoviruses, including Thogoto virus. Thus, Mx1(+) A2G mice are apparently resistant to infection following needle- or tick-borne virus challenge. However, tick-borne challenge and, to a lesser degree, injection of virus mixed with tick salivary gland extract resulted in virus transmission to uninfected ticks feeding on the A2G mice. The data indicate that immunomodulatory components in tick saliva can overcome a natural antiviral mechanism.

Animals↗
PubMed1995

Mx1 but not MxA confers resistance against tick-borne Dhori virus in mice.

The interferon-induced nuclear Mx1 protein is responsible for innate resistance of mice to influenza virus. It has been unclear why mice are equipped with a powerful and specific defense mechanism against influenza viruses for which they are not natural hosts. Here, we show that Dhori virus, an influenza-like virus transmitted by ticks and known to infect small mammals, is sensitive to the Mx1 resistance mechanism. Influenza virus-susceptible BALB/c and C57BL/6 mice (lacking a functional Mx1 gene) developed severe disease symptoms and died within a few days after intraperitoneal infection with a lethal dose of Dhori virus. In contrast, Mx1(+)-congenic, influenza virus-resistant BALB.A2G-Mx1 and B6.A2G-Mx1 mice remained healthy and survived. The Mx1 resistance phenotype was expressed in cultured peritoneal macrophages and interferon-treated embryonic cells obtained from these mice. Moreover, stable lines of transfected mouse 3T3 cells constitutively expressing Mx1 protein were protected from Dhori virus infection. The MxA protein of human cells shows a high degree of sequence similarity to Mx1 but, unlike Mx1, inhibits a broad range of RNA viruses. Transgenic mice that permanently express the human MxA protein in various organs became resistant to infection with Thogoto virus but remained fully susceptible to Dhori virus. These in vivo results show that DHO virus is unique in being resistant to human MxA but susceptible to mouse Mx1 protein. They further indicate that the Mx1 system functions as a potent defense mechanism against tick-borne influenza-like viruses in mice.

3T3 Cells↗
PubMed2004

Thogoto virus lacking interferon-antagonistic protein ML is strongly attenuated in newborn Mx1-positive but not Mx1-negative mice.

The Thogoto virus ML protein suppresses interferon synthesis in infected cells. Nevertheless, a virus mutant lacking ML remained highly pathogenic in standard laboratory mice. It was strongly attenuated, however, in mice carrying the interferon-responsive Mx1 gene found in wild mice, demonstrating that enhanced interferon synthesis is protective only if appropriate antiviral effector molecules are present. Our study shows that the virulence-enhancing effects of some viral interferon antagonists may escape detection in conventional animal models.

Animals↗
PubMed2005

Constitutive expression of Atlantic salmon Mx1 protein in CHSE-214 cells confers resistance to infectious salmon anaemia virus.

Infectious salmon anaemia (ISA) is a highly fatal viral disease affecting marine-farmed Atlantic salmon which is caused by ISA virus (ISAV), a fish orthomyxovirus that has recently been assigned to the new genus Isavirus within the family Orthomyxoviridae. Mx proteins are among the interferon (IFN)-induced proteins responsible for the development of an antiviral state in vertebrate cells. We used real-time reverse transcription-polymerase chain reaction (RT-PCR) and Chinook salmon embryo (CHSE-214) cells constitutively expressing Atlantic salmon Mx1 protein (ASMx1) to examine the antiviral properties of ASMx1 against two ISAV strains, NBISA01 and HKS-36, having phenotypically different growth properties (cytopathic vs non-cytopathic) in the CHSE-214 cell line. We present evidence that ISAV is sensitive to ASMx1. CHSE-214 cells constitutively expressing ASMx1 showed increased resistance to infection with the cytopathic ISAV strain NBISA01, manifested as delayed development of cytopathic effects (CPE) and significant reduction in the severity of CPE, as well as a 10-fold reduction in virus yield. However, by real-time RT-PCR we observed no significant difference in the mean threshold cycle (Ct) values of ISAV RNA levels, suggesting that the ASMx1 activity on ISAV occurs at the post-transcription steps of virus replication, possibly in the cytoplasm.

Animals↗
PubMed1999

Interferon-induced antiviral resistance. A mathematical model of regulation of Mx1 protein induction and action.

Influenza A virus and various single-stranded RNA viruses have been reported to be blocked by IFN-stimulated Mx protein. Here we present a mathematical model of regulation of mouse Mx1 protein induction and action under influenza infection. Parameter estimates are derived from published experimental data. Numerical solutions of the model equations completely correspond to experimental data. The model is used to analyse the role of virus- and interferon-mediated expression of Mx1 in maintenance of antiviral state. The study suggests that virus- and IFN-induced Mx1 proteins act on different stages of intracellular ontogenesis of influenza virus and these actions result in different efficacy of cell protection. The model demonstrates that the synergistic action of inteferon and virus in regulation of Mx1 gene expression is the important factor of antiviral resistance. The results of simulation permit to assume that the active form of Mx1 protein is trimer.

Animals↗
PubMed1992

Transgenic pigs carrying cDNA copies encoding the murine Mx1 protein which confers resistance to influenza virus infection.

An important aspect of gene transfer into farm animals is the improvement of disease resistance. The mouse Mx1 protein is known to be sufficient to confer resistance to influenza viruses. Gene constructs containing the mouse Mx1 cDNA controlled by the human metallothionein IIA promoter (hMTIIA::Mx), the SV40 early enhancer/promoter region (SV40::Mx) and the mouse Mx1 promoter (mMx::Mx) were transferred into pigs. The results of the gene transfer experiments with the hMTIIA::Mx and the SV40::Mx constructs indicate that the permanent high-level synthesis of Mx1 might be deleterious to the organism: the gene transfer efficiency was surprisingly low, and all transgenic piglets born had rearrangements in their transgene copies that abolished protein synthesis. The use of the interferon (IFN)- and virus-inducible mMx::Mx construct resulted in normal gene transfer efficiency. Two transgenic pig lines could be established which expressed IFN-inducible mouse Mx1 mRNA. Extensive protein analysis did not detect mouse Mx1 in IFN-treated transgenic animals.

Animals↗
PubMed2006

Genomic structure, promoter analysis, and expression of the porcine (Sus scrofa) Mx1 gene.

Allelic polymorphisms at the mouse Mx1 locus affect the probability of survival after experimental influenzal disease, raising the possibility that marker-assisted selection using the homologous locus could improve the innate resistance of pigs to natural influenza infections. Several issues need to be resolved before efficient large scale screening of the allelic polymorphism at the porcine (Sus scrofa) Mx1 locus can be implemented. First, the Mx1 genomic structure has to be established and sufficient flanking intronic sequences have to be gathered to enable simple PCR amplification of the coding portions of the gene. Then, a basic knowledge of the promoter region needs to be obtained as an allelic variation there can significantly alter absolute levels and/or tissue-specificity of MX protein expression. The results gathered here show that the porcine Mx1 gene and promoter share the major structural and functional characteristics displayed by their homologs described in cattle, mouse, chicken, and man. The crucial function of the proximal interferon-sensitive response elements motif for gene expression is also demonstrated. The sequence data compiled here will allow an extensive analysis of the polymorphisms present among the widest spectrum possible of porcine breeds with the aim to identify an Mx1 allele providing antiviral resistance.

Amino Acid Sequence↗
PubMed2006

Expression of MHC class I pathway genes in response to infectious salmon anaemia virus in Atlantic salmon (Salmo salar L.) cells.

Infectious salmon anaemia virus (ISAV) is the causative agent of an important viral disease threatening Atlantic salmon aquaculture. Although its structure and pathogenesis is well described little is known about its immunomodulatory effects on the host. Cellular immunity is critical in the host control of virus infections, an event attributable to antigen presentation through the MHC class I pathway, whose genes are transcriptionally activated by interferons (IFN) and other cytokines. In this study we analysed the regulation and kinetics of key genes in the salmon MHC class I pathway in relation to type I IFN during ISAV infection and poly I:C stimulation in the permissive Atlantic salmon kidney cell line (ASK). As measured by quantitative real-time PCR, ISAV induced an mRNA shut-off equivalent to 2.5-5.5-fold reduced levels of housekeeping genes at 7 days post infection. Relative to this shut-off (by normalising to beta-actin) transcription increased to peak levels at 2.8-fold for MHC class I, 10-fold for beta 2 microglobulin (beta 2m), 5.9-fold for the peptide transporter ABCB2, 8.8-fold for the proteasome component PSMB8 and 4.6-fold for the proteasome component PSMB9, presumably by activation of the IFN system as a 26-fold induction was observed for type I IFN-alpha. Expression of Mx protein was also induced 17-fold at peak level. Similar kinetics and activation levels of these genes were seen in poly I:C stimulated cells. We also isolated the salmon MHC class I UBA*0301 promoter and identified a conserved interferon-stimulated response element (ISRE) and GAAA-elements plus several GAS- and IRF-sites, all supporting IFN-inducible properties. In summary, we demonstrate a concerted induction of the MHC class I pathway and type I IFN by ISAV comparable to levels induced by the synthetic double-stranded RNA (dsRNA) poly I:C. Thus, unlike influenza and several other viruses ISAV does not seem to interfere with MHC and IFN expression.

Animals↗
PubMed2002

Effect of double-stranded RNA and interferon on the antiviral activity of Atlantic salmon cells against infectious salmon anemia virus and infectious pancreatic necrosis virus.

Type I interferons (IFN) establish an antiviral state in vertebrate cells by inducing expression of Mx and other antiviral proteins. We have studied the effect of Atlantic salmon interferon-like activity (AS-IFN) and poly I:C on the Mx protein expression and antiviral activity against infectious salmon anaemia virus (ISAV) and infectious pancreatic necrosis virus (IPNV) in the Atlantic salmon cell lines SHK-1 and TO. The double-stranded RNA poly I:C is an inducer of type I IFN in vertebrates. A cell cytotoxicity assay and measurements of virus yield were used to measure protection of cells against virus infection. Maximal induction of Mx protein in TO and SHK-1 cells occurred 48 h after poly I:C stimulation and 24 h after AS-IFN stimulation. TO cells pretreated with AS-IFN or poly I:C were protected from infection with IPNV 24 to 96 h after stimulation. Poly I:C or AS-IFN induced a minor protection against ISAV infection in SHK-1 cells, but no protection was induced against ISAV in TO cells. Western blot analysis showed that ISAV induced expression of Mx protein in TO and SHK-1 cells whereas IPNV did not induce Mx protein expression. These results suggest that ISAV and IPNV have very different sensitivities to IFN-induced antiviral activity and have developed different strategies to avoid the IFN-system of Atlantic salmon. Moreover, Atlantic salmon Mx protein appears not to inhibit replication of ISAV.

Animals↗
PubMed1988

Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation.

The interferon-regulated mouse Mx gene encodes the 72-kilodalton nuclear Mx protein that selectively inhibits influenza virus replication. Mice carrying Mx+ alleles synthesize Mx protein and resist influenza virus infection, whereas mice homozygous for Mx- alleles fail to synthesize Mx protein and, as a consequence, are influenza virus susceptible. Southern blot analysis allowed us to define the following three distinct Mx restriction fragment length polymorphism (RFLP) types among classical inbred strains: RFLP type 1 in the Mx+ strains A2G and SL/NiA, RFLP type 2 in BALB/c and 33 other Mx- strains, and RFLP type 3 in CBA/J and 2 other Mx- strains. cDNA clones of Mx mRNAs from BALB/c and CBA/J cells were isolated, and their sequences were compared with that of the wild-type Mx mRNA of strain A2G. Mx mRNA of BALB/c mice has 424 nucleotides absent from the coding region, resulting in a frame shift and premature termination of Mx protein. The missing sequences correspond exactly to Mx exons 9 through 11. These three exons, together with some flanking intron sequences, are deleted from the genomes of all Mx RFLP type 2 strains. The Mx- phenotype of the Mx RFLP type 3 strain CBA/J is due to a point mutation that converts the lysine codon in position 389 to a termination codon. Mx RFLP type 3 strains have an extra HindIII site which maps to an intron and thus probably does not affect the coding capacity of Mx mRNA. We further show that the Mx mRNA levels in interferon-treated BALB/c and CBA/J cells are about 15-fold lower than in similarly treated Mx+ cells. This is probably due to decreased metabolic stabilities of the mutant mRNAs.

Animals↗
PubMed1992

Resistance to influenza virus infection of Mx transgenic mice expressing Mx protein under the control of two constitutive promoters.

Transgenic mice constitutively expressing in the brain the influenza virus resistance protein Mx1 controlled by the HMG (3-hydroxy-3-methylglutaryl coenzyme A reductase) promoter showed specific resistance against the neurotropic influenza A virus strain NWS. Control mice of the A2G strain express Mx1 protein in all organs, but only after induction by interferon type I upon or without viral infection. The extent of specific resistance in transgenic mice of the best-expressing line reached about two-thirds that of controls, most likely because of considerably less total-body Mx protein activity in the transgenic mice. Thus, the theoretical advantage in these mice of the continuous presence of Mx protein with early inhibitory potential to viral replication was apparently offset by restricted organ expression. Strong evidence that the Mx1 protein on its own is a specific anti-influenza A virus agent and that its efficiency in the experimental setting is independent of interferon actions could be derived from the treatment of experimental and control mice with anti-interferon antibodies at the time of virus tests. Whereas in A2G mice, Mx1 mRNA and Mx1 protein synthesis were abolished and viral resistance was markedly reduced or abolished, resistance in the transgenic mice persisted to almost the same degree. Transgenic mice generated with a mouse albumin/Mx1 cDNA construct showed liver-specific expression. However, in two expressing transgenic lines, Mx1 protein synthesis was suppressed after a few months. The mechanism of suppression could not be elucidated, but increasing methylation of the transgene's coding region was not the cause. It is possible that continuous Mx1 protein expression in the liver is less well tolerated than that in the brain. Whether this partial suppression and, with the HMG promoter, restricted organ expression are the organism's responses to interference of Mx1 with normal cellular activities such as nucleocytoplasmic transport of RNA and proteins cannot be determined until the molecular mechanisms of antiviral activity of Mx1 protein are understood.

Animals↗
PubMed2005

Poly I:C induces an antiviral state against Ictalurid Herpesvirus 1 and Mx1 transcription in the channel catfish (Ictalurus punctatus).

In vivo studies were carried out to investigate the protective effect of the interferon inducer poly I:C against channel catfish virus (CCV). Channel catfish were stimulated by intraperitoneal injection of 50 microg of poly I:C or PBS at various days prior to immersion challenge with CCV. Mortality in the poly I:C group was significantly reduced from 70% to 3% at day 1 compared to the PBS controls. Mortality increased at day 3 but was still significantly different from the PBS controls. Mx1 transcription was significantly higher only at day 1. In an additional study Mx1 transcription was monitored in the liver, kidney, gills, spleen, and intestine at various time points post-stimulation with either poly I:C or CCV. Mx1 mRNA was significantly elevated in all organs only at day 1 post-injection with poly I:C. In response to CCV, Mx1 transcription was not significantly elevated until day 3 post-challenge, but remained elevated in certain organs until day 7.

Animals↗
PubMed1975

Host-cell antigen potentiated by incomplete growth cycle of influenza virus.

Lysis of Ehrlich ascites tumor cells in mice was induced with the Hong Kong influenza A-strain HKH virus not previously adapted to the tumor. Despite high pathogenicity of HKH, mice not genetically resistant to the lethal action of myxoviruses survived the actue phase of oncolysis. Virus infection of tumor cells resulted in high titers of hemagglutinin with low infectivity which indicated incomplete virus growth. Serial passages of HKH in Ehrlich ascites tumors failed. HKH oncolysates induced solid antitumor immunity in several mouse strains, including those fully susceptible to the virus. The immunizing power of HKH oncolysates could be abolished by mouse antibody against egg-grown HKH (H3, N2) but not by antiserum raised aganist TUR virus (Havl, Nav3).

Animals↗
PubMed1975

Early events in myxovirus replication: immunofluorescent spots.

Indirect immunofluorescent staining of Ehrlich ascites tumor cells infected with two influenza A strains, WSA (HON1) and TUR (Hav1 Nav3), revealed early fluorescent spots which became detectable in the cytoplasm within 30 minutes of infection, before the nucleoprotein antigen appeared in the nucleus. These spots seemed to be linked to some structural antigen of the virus not identical with hemagglutinin, neuraminidase, or nucleoprotein. Their formation was not inhibited by actinomycin, p-fluorophenylalanine or amantadine in concentrations sufficient to block viral replication; amantadine led to an altered time course of spot evolution and to the emergence of coarser spots. The exact serologic specificity of early spots remains to be worked out but appears to differ from that of known influenza A antigens.

Amantadine↗
PubMed1965

CYTOCHEMICAL AND ELECTRON MICROSCOPICAL OBSERVATIONS ON THE PRESENCE AND ORIGIN OF ADENOSINE TRIPHOSPHATASE-LIKE ACTIVITY AT THE SURFACE OF TWO MYXOVIRUSES.

Dawson, C. R. (The Middlesex Hospital Medical School, London, England), M. A. Epstein, and K. Hummeler. Cytochemical and electron microscopical observations on the presence and origin of adenosine triphosphatase-like activity at the surface of two myxoviruses. J. Bacteriol. 89:1526-1532. 1965.-HeLa cells infected with either fowl plague virus (FPV) or Newcastle disease virus (NDV) were examined in thin sections by electron microscopy. Preparations were studied both after direct fixation and embedding and after the application of cytochemical staining for enzymes splitting adenosine triphosphate. Viral particles were identified by their size and characteristic structure, and were found to form at the cell surface by budding out through structurally altered plasmalemma. After cytochemical staining for adenosine triphosphatase activity, extracellular FPV or NDV particles lying close against cell membranes with enzyme activity likewise carried this function, whereas those particles which were associated with cell surfaces without reaction product were themselves free from it. This correspondence between enzyme function in cell membranes and the outer viral membranes of newly formed particles adjacent to them indicates that surface enzymatic capability of the host cell survives even when the cell membrane undergoes morphological and antigenic alteration into myxovirus outer membrane.

Adenosine Triphosphatases↗
PubMed2005

Characterization of snakehead rhabdovirus infection in zebrafish (Danio rerio).

The zebrafish, Danio rerio, has become recognized as a valuable model for the study of development, genetics, and toxicology. Recently, the zebrafish has been recognized as a useful model for infectious disease and immunity. In this study, the pathogenesis and antiviral immune response of zebrafish to experimental snakehead rhabdovirus (SHRV) infection was characterized. Zebrafish 24 h postfertilization to 30 days postfertilization were susceptible to infection by immersion in 10(6) 50% tissue culture infective doses (TCID50) of SHRV/ml, and adult zebrafish were susceptible to infection by intraperitoneal (i.p.) injection of 10(5) TCID50 of SHRV/ml. Mortalities exceeded 40% in infected fish, and clinical presentation of infection included petechial hemorrhaging, redness of the abdomen, and erratic swim behavior. Virus reisolation and reverse transcription-PCR analysis of the viral nucleocapsid gene confirmed the presence of SHRV. Histological sections of moribund embryonic and juvenile fish revealed necrosis of the pharyngeal epithelium and liver, in addition to congestion of the swim bladder by cell debris. Histopathology in adult fish injected i.p. was confined to the site of injection. The antiviral response in zebrafish was monitored by quantitative real-time PCR analysis of zebrafish interferon (IFN) and Mx expression. IFN and Mx levels were elevated in zebrafish exposed to SHRV, although expression and intensity differed with age and route of infection. This study is the first to examine the pathogenesis of SHRV infection in zebrafish. Furthermore, this study is the first to describe experimental infection of zebrafish embryos with a viral pathogen, which will be important for future experiments involving targeted gene disruption and forward genetic screens.

Animals↗