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At least 19 recordsLinked to original sources
PubMedDate not supplied

[The isolation of Dhori viruses (Orthomyxoviridae, Thogotovirus) and Crimean-Congo hemorrhagic fever virus (Bunyaviridae, Nairovirus) from the hare (Lepus europaeus) and its ticks Hyalomma marginatum in the middle zone of the Volga delta, Astrakhan region, 2001].

In August, 2001, in the middle zone of the delta of the Volga River, the Astrakhan region, during investigation of the natural foci of West Nile fever and Crimean--Congo hemorrhagic fever (CCHF), the material from the hare (Lepus europaeus, Pallas, 1778 (Lagomorpha, Leporidae) and collected from it the ticks Hyalomna marginatum Koch 1844, was obtained. 4 strains of Dhori virus (Orthomyxoviridae, Thogotovirus) and 2 strains of CCHF virus (Bunyaviridae, Nairovirus) were isolated. This is the first isolation of Thogotovirus genus virus from the wild vertebrates. Considering the overlap of the Dhori virus and CCHF virus areas, similar ecology and the isolation both viruses from the same pool of the ticks, the necessity for the use of the test-system for indication of the viruses, differential diagnosis and accumulation of the data concerning the role of Dhori virus in the human and farm animals pathology is discussed.

Animals↗
PubMed2005

Araguari virus, a new member of the family Orthomyxoviridae: serologic, ultrastructural, and molecular characterization.

This paper reports the results of serologic, structural, biochemical, and genetic studies indicating that Araguari virus, a previously unassigned viral agent, is a member of the family Orthomyxoviridae and genus Thogotovirus. Araguari virus has six RNA fragments; biologically, it shares several properties with other viruses in the family Orthomyxoviridae. Nucleotide sequencing of the RNA segments 4 (glycoprotein) and 5 (nucleoprotein) of Araguari virus aligned with the orthomyxoviruses, showing the closest relationship with Thogoto virus (sequence similarity = 61.9% and 69.1%, respectively, for glycoprotein and nucleoprotein), but also sharing a more distant similarity with Dhori and Influenza C viruses, especially for the glycoprotein gene. Based on these results, we propose that Araguari virus should be assigned as a new member of the family Orthomyxoviridae and genus Thogotovirus.

Animals↗
PubMed1997

The fourth genus in the Orthomyxoviridae: sequence analyses of two Thogoto virus polymerase proteins and comparison with influenza viruses.

The tick-borne Thogoto virus (THOV) is the type species of a newly recognized fourth genus, Thogotovirus, in the family Orthomyxoviridae. Because of the distant relationship of THOV with the influenza viruses, determination of its genomic information can potentially be used to identify important domains in influenza virus proteins. We have determined the complete nucleotide sequence of the second longest RNA segment of THOV. The molecule comprises 2212 nucleotides with a single large open reading frame encoding a protein of 710 amino acids, estimated Mr 81,284. The protein shares 77% amino acid similarity with the PB1-like protein of Dhori virus, a related tick-borne virus, and 50-53% with the PB1 polymerase proteins of influenza virus A, B and C. All the motifs characteristic of RNA-dependent polymerases were identified including the SSDD motif common to all RNA-dependent RNA polymerases, indicating that the THOV protein is functionally analogous to the influenza virus PB1 proteins and involved in chain elongation. We also report the corrected sequence of the third longest RNA segment of THOV, encoding a protein which shares 44-47% amino acid similarity with the PA-like polymerase proteins of influenza virus A, B and C. The biological significance of conserved domains in these orthomyxovirid proteins is discussed.

Amino Acid Sequence↗
PubMed1997

Mx1 sensitivity: Batken virus is an orthomyxovirus closely related to Dhori virus.

Batken virus, isolated from mosquitoes and ticks, was tentatively classified as a member of the family Bunyaviridae. Here we show that Batken virus is inhibited by the interferon-induced Mx1 protein of mice which selectively blocks the growth of orthomyxoviruses, including Thogoto and Dhori viruses. Furthermore, we show that Batken virus multiplication is characterized by accumulation of viral proteins in the nucleus and by budding of viral particles from the cell surface. Serological cross-reactions between Batken and Dhori viruses revealed a phylogenetic relationship of these viruses, as previously also proposed by D. K. Lvov. Fragments of the Batken virus glycoprotein and nucleoprotein genes were amplified by RT-PCR. The deduced amino acid sequences were similar to the corresponding Dhori virus sequences. Therefore, Batken virus should be classified into the newly established genus Thogotovirus of the family Orthomyxoviridae. Finally, our results demonstrate that Mx1 susceptibility of orthomyxoviruses is a reliable marker in the hunt for new family members.

Amino Acid Sequence↗
PubMed2001

Antigenic variation among isolates of infectious salmon anaemia virus correlates with genetic variation of the viral haemagglutinin gene.

Infectious salmon anaemia virus (ISAV), an orthomyxovirus-like virus, is an important fish pathogen in marine aquaculture. Virus neutralization of 24 ISAV isolates in the TO cell line using rabbit antisera to the whole virus and comparative sequence analysis of their haemagglutinin (HA) genes have allowed elaboration on the variation of ISAV isolates. The 24 viruses were neutralized to varying degrees, revealing two major antigenic groups, one American and one European. Sequence analysis of the HA gene also revealed two groups of viruses (genotypes) that correlated with the antigenic groupings. The two HA subtypes had nucleotide sequence identity of only < or =79.4% and amino acid sequence identity of < or =84.5% whereas, within each subtype, the sequence identities were 90.7% or higher. This grouping was also evident upon phylogenetic analysis, which revealed two distinct phylogenetic families. Between the two groups, the amino acid sequence was most variable in the C-terminal region and included deletions of 4-16 amino acids in all isolates relative to ISAV isolate RPC/NB-980 280-2. In order to view the relationships among these sequences and the HA sequences of the established orthomyxoviruses, a second phylogenetic tree was constructed which showed the ISAV sequences to be more closely related to sequences from Influenzavirus A and Influenzavirus B than to sequences from Influenzavirus C and Thogotovirus. The extensive deletions in the gene of European ISAV isolates lead us to speculate that the archetypal ISAV was probably of Canadian origin.

Amino Acid Sequence↗
PubMed1996

Amblyomma variegatum (Acari: Ixodidae): mechanism and control of arbovirus secretion in tick saliva.

Saliva is considered to be the conduit by which pathogens are transmitted from blood-sucking arthropod vectors to their vertebrate hosts, but supporting evidence for this is fragmentary. To determine if Thogoto (THO) virus, a tick-borne member of the influenza virus family, is transmitted via tick saliva, and whether virus replication is a prerequisite for such transmission, two experimental conditions were compared: (1) "biological transmission" and (2) "mechanical transmission." In (1), THO virus was allowed to infect and replicate in a natural vector, Amblyomma variegatum: virus was detected in saliva collected from 3/22 (14%) ticks. In (2), virus was inoculated directly into the hemocoel with the drug used to induce salivation and saliva was collected immediately to preclude the possibility of virus replication: virus was detected in saliva collected from 31/170 (18%) ticks. The results demonstrate that THO virus is secreted in tick saliva and that virus can pass from the hemolymph to the salivary glands independently of viral replication within the tick. The comparatively low numbers of ticks that yielded virus-positive saliva samples together with the results from assays of serial saliva samples suggested that virus secretion may not be a continuous process during salivation. Ticks in which THO virus had established an infection showed an impaired secretory response compared with uninfected ticks and ticks used for mechanical transmission.

Analysis of Variance↗
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↗
PubMed1995

Immune protection conferred by the baculovirus-related glycoprotein of Thogoto virus (Orthomyxoviridae).

The coding region of segment 4 of Thogoto (THO) virus, a tick-borne member of the Orthomyxoviridae, was expressed in a baculovirus system under the control of the polyhedrin promoter. This construct expressed authentic envelope glycoprotein as determined by size and antigenic reactivity with a panel of monoclonal antibodies (MAbs). Immunization of hamsters with Spodoptera frugiperda (Sf21) cells infected with the recombinant baculovirus induced neutralizing and protective antibodies against virus challenge; control hamsters developed clinical disease with high-titer viremia 3 days postchallenge. In contrast to hamsters, guinea pigs are comparatively resistant to THO virus infection but support nonviremic transmission between cofeeding infected and uninfected ticks. However, when uninfected ticks fed on guinea pigs immunized with the baculovirus recombinant, only 2% became infected following virus challenge of the animals compared to 26% of ticks on control nonimmune guinea pigs. Furthermore, neutralizing MAbs specific for THO viral glycoprotein protected mice against lethal challenge with THO virus; nonneutralizing MAbs specific for the glycoprotein, which inhibit THO viral agglutinating activity, did not induce a protective response. Thus at least in the murine model, protective immunity is conferred by antibodies directed against the neutralizing epitope(s) of the baculovirus-related glycoprotein of THO virus.

Animals↗
PubMed1998

A classical bipartite nuclear localization signal on Thogoto and influenza A virus nucleoproteins.

We have previously shown that the nucleoprotein (NP) of Thogoto virus (THOV), a tick-borne member of the Orthomyxoviridae family, accumulates in the cell nucleus. Here we demonstrate that THOV NP contains a motif (KRxxxxxxxxxKTKK) at amino acid positions 179-193 that represents a classical bipartite nuclear localization signal (NLS). This sequence motif (named cNLS) was able to translocate a cytoplasmic 80-kDa reporter protein into the nucleus. Targeted mutations substituting lysines for alanines in the downstream cluster of the bipartite motif abolished the capacity of cNLS to mediate nuclear import. In contrast, identical mutations had no effect on nuclear localization when introduced into THOV NP, indicating that additional transport signals are present in NP. Amino-acid sequence comparisons revealed that THOV NP lacks the N-terminal nonconvential NLS (named here nNLS), which has been implicated in nuclear import of influenza A virus NP. Accordingly, THOV NP failed to interact in coprecipitation assays with the cellular NPI-1/3 transport factors of the karyopherin alpha family. A highly conserved motif identified in THOV NP was the so-called nuclear accumulation sequence (NAS). Mutating NAS alone, or in combination with cNLS, had no gross effect on the intracellular distribution of the protein, indicating that a functional NAS is not required for nuclear accumulation of THOV NP in mammalian cells. We also studied nuclear transport of influenza A/PR/8/34 virus NP. Interestingly, we found a cNLS motif at amino acid positions 198-216 in addition to the previously described nonconventional nNLS. To further assess the functional role of cNLS, nNLS, and NAS, we analyzed single, double, and triple mutants of influenza A virus NP. When nNLS was destroyed, the protein stayed in the cytoplasm as expected. When NAS was disrupted in addition to nNLS, the double mutant accumulated in the nucleus, suggesting that cNLS was active. Indeed, when cNLS was also inactivated, the triple mutant protein localized again predominantly to the cytoplasm. These findings suggest that NP of orthomyxoviruses have two independent NLSs, namely cNLS and nNLS. They further suggest that NAS and NLSs may assume opposing roles in nucleocytoplasmic transport of NP.

Amino Acid Sequence↗
PubMed2004

Orthomyxovirus replication, transcription, and polyadenylation.

Efficient in vitro and in vivo systems are now in place to study the role of viral proteins in replication and/or transcription, the regulation of these processes, polyadenylation of viral mRNAs, the viral promoter structures, or the significance of noncoding regions for virus replication. In this chapter, we review the status of current knowledge of the orthomyxovirus RNA synthesis.

DNA-Directed RNA Polymerases↗
PubMed1996

Thogoto and Dhori virus replication is blocked by inhibitors of cellular polymerase II activity but does not cause shutoff of host cell protein synthesis.

Tick-transmitted Thogoto and Dhori viruses share structural and genetic properties with the influenza viruses. Here, we compare different steps of their replication cycle in mammalian cells in comparison with influenza A virus. Viral antigens of both viruses accumulated in the nuclei of infected cells, suggesting a nuclear phase of viral replication. Furthermore, as observed with influenza viruses, transcription of Thogoto and Dhori viruses was inhibited by alpha-amanitin and actinomycin D, suggesting a dependence of viral transcription on cellular RNA polymerase II activity. In contrast to influenza viruses, Thogoto and Dhori virus infection did not lead to down-regulation of cellular protein synthesis indicating marked differences regarding the fate of infected cells.

3T3 Cells↗
PubMed1997

Conserved vRNA end sequences of Thogoto-orthomyxovirus suggest a new panhandle structure.

Panhandles are dsRNA structures formed by conserved sequences at the 5' and 3' ends of the influenza virus genomic RNA. They consist of two stems separated by a flexible bulge and serve as promoter for the viral polymerase. In the outer stem, melting of base pairs is a prerequisite for initiation of transcription. We compared the terminal sequences of Thogoto virus (THOV), a tick-borne orthomyxovirus, with those of influenza virus. Despite their overall similarity, the first U downstream of the 5' end of the panhandle (position 3 in influenza virus) is found at position 8 in the THOV sequence. This shift from position 3 to position 8 results in a radical change of the predicted secondary structure. In the outer stem, intra-strand base pairings are clearly favoured above inter-strand hybridizations. As this secondary structure can explain the functioning of a mutant promoter of influenza virus with twice the activity of the wild-type, we propose a general validity of our "hook-like" panhandle structure.

Base Sequence↗
PubMed1999

PB2 polymerase subunit of Thogoto virus (Orthomyxoviridae family).

Thogoto virus (THOV) represents a new genus in the family Orthomyxoviridae. The three polymerase subunits PB1, PB2, and PA initiate transcription by a unique cap-stealing mechanism that involves the cleavage of only the m(7)GpppAm structure from cellular hnRNAs. Here, we report the cloning of the longest genomic segment of THOV coding for PB2. It comprises 2,375 nucleotides encoding a single large open reading frame flanked by the conserved terminal regions typical for orthomyxoviruses. The deduced amino acid sequence corresponds to a protein of 769 amino acids, with an estimated Mr of 88,042. Expression of the PB2 cDNA in mammalian cells revealed nuclear accumulation of the recombinant protein, consistent with the replication of THOV in the cell nucleus.

Amino Acid Sequence↗
PubMed2005

Thogoto virus ML protein suppresses IRF3 function.

The Thogoto virus (THOV) is a member of the family Orthomyxoviridae. It prevents induction of alpha/beta interferons (IFN) in cell culture and in vivo via the action of the viral ML protein. Phenotypically, the effect of THOV ML resembles that of the NS1 protein of influenza A virus (FLUAV) in that it blocks the expression of IFN genes. IFN expression depends on IFN regulatory factor 3 (IRF3). Upon activation, IRF3 forms homodimers and accumulates in the nucleus where it binds the transcriptional coactivator CREB-binding protein (CBP). Here, we show that expression of ML blocked the transcriptional activity of IRF3 after stimulation by virus infection. Further biochemical analysis revealed that ML acts by blocking IRF3 dimerization and association with CBP. Surprisingly, however, ML did not interfere with the nuclear transport of IRF3. Thus, the action of ML differs strikingly from that of FLUAV NS1 that prevents IFN induction by retaining IRF3 in the cytoplasm.

Animals↗
PubMedDate not supplied

Rhipicephalus appendiculatus (Acari: Ixodidae): dynamics of Thogoto virus infection in female ticks during feeding on guinea pigs.

Engorged nymphs (Rhipicephalus appendiculatus) were inoculated parenterally with Thogoto (THO) virus (approximately 1 microl per nymph; 10(6)-10(7) PFU/ml). The adult females which resulted were used as the source of infected ticks for this study. Hemolymph, salivary glands, synganglion, gut, ovary, and Malpighian tubules were collected on each day of the blood meal and titrated for THO virus by plaque assay. The percent of tissues infected with virus was 16% or less on the day of attachment. Percent infection rose for all tissues throughout 6-7 days of feeding, reaching 40-100% infection during the rapid phase of engorgement. For the first 4 days of feeding, virus titer in the synganglion was higher than in salivary glands (means of 6.4-34.7 PFU/synganglion and 1.6-8.8 PFU/salivary gland pair). From days 5-7, virus titer was generally higher in the salivary gland than the synganglion (means of 422, 408, and 817 PFU/gland pair and means of 62, 811, and 9 PFU/synganglion). However, because a salivary gland pair is much heavier than a synganglion, the virus concentration in the synganglion was much higher than in the salivary gland during the slow phase of feeding. During the rapid phase of feeding, the difference in virus titer between the synganglion and salivary gland reduced. This difference between the early and late stages of feeding may explain why a previous study [J. Gen. Virol. 70 (1989) 1093], using immunofluorescence and immuno-gold labelling, failed to detect virus in the salivary gland early in feeding. These data provide evidence to explain that R. appendiculatus can transmit THO virus within 24h of attachment, an important epidemiological finding.

Animals↗
PubMed2000

Rescue of synthetic RNAs into thogoto and influenza A virus particles using core proteins purified from Thogoto virus.

The ribonucleoprotein (RNP) complexes of Thogoto virus (THOV), a tick-borne orthomyxovirus, have been purified from detergent-lysed virions. The purified RNPs were then disrupted by centrifugation through a CsCl-glycerol gradient to obtain fractions highly enriched in nucleoprotein (NP) and virtually devoid of viral genomic RNA. When these NP-enriched fractions were incubated with a synthetic THOV-like RNA, and the mixtures were transfected into THOV-infected cells, the synthetic RNA was expressed and packaged into THOV particles. Similarly, hybrid mixtures containing purified THOV NP and influenza A virus synthetic RNAs (either a model CAT RNA or a gene encoding the viral neuraminidase), were prepared and transfected into influenza A virus-infected cells. The synthetic CAT RNA, was shown to be expressed and packaged into virus particles, and the neuraminidase gene was rescued into influenza virions. These data are discussed in terms of the similarities observed between THOV and influenza A virus and the potential application of the THOV purified proteins for rescuing synthetic genes into infectious viruses.

Animals↗
PubMed2003

Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses.

Most RNA viruses that lack a DNA phase replicate in the cytoplasm. However, several negative-stranded RNA viruses such as influenza, Thogoto, and Borna disease viruses replicate their RNAs in the nucleus, taking advantage of the host cell's nuclear machinery. A challenge faced by these viruses is the trafficking of viral components into and out of the nucleus through the nuclear membrane. The genomic RNAs of these viruses associate with proteins to form large complexes called viral ribonucleoproteins (vRNPs), which exceed the size limit for passive diffusion through the nuclear pore complex (NPC). To insure efficient transport across the nuclear membrane, these viruses use nuclear import and export signals exposed on the vRNPs. These signals recruit the cellular import and export complexes, which are responsible for the translocation of the vRNPs through the NPC. The ability to control the direction of vRNP trafficking throughout the viral life cycle is critical. Various mechanisms, ranging from simple post-translational modification to complex, sequential masking-and-exposure of localization signals, are used to insure the proper movement of the vRNPs.

Active Transport, Cell Nucleus↗
PubMed1998

In vivo reconstitution of active Thogoto virus polymerase: assays for the compatibility with other orthomyxovirus core proteins and template RNAs.

Tick-borne Thogoto virus (THOV), the prototype of a new genus in the Orthomyxoviridae family, contains six single-stranded RNA segments of negative polarity. Four of them encode gene products that correspond to the influenza virus PB1, PB2, PA and NP core proteins. Here we describe an in vivo system in which the expression of a THOV model RNA is driven by THOV core proteins synthesized from cloned cDNAs. Our results demonstrated the biological activity of our cloned genes and showed that the three polymerase subunits and the NP are required for gene expression. For comparison, we also used the in vivo reconstituted systems of the influenza A and B viruses. None of the polymerase or NP proteins was active in a heterologous orthomyxovirus core, indicating a high specificity in core assembly and/or function. Interestingly, the THOV polymerase did not recognize the influenza A virus promoter and vice versa.

Cloning, Molecular↗