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At least 19 recordsLinked to original sources
PubMed1998

Non-rabies Lyssavirus human encephalitis from fruit bats: Australian bat Lyssavirus (pteropid Lyssavirus) infection.

A 39-year-old woman died of encephalitis a few weeks after being scratched by fruit bats. Autopsy disclosed meningoencephalomyelitis, and revealed neuronal intracytoplasmic inclusions which had similarities to Negri bodies of rabies. Laboratory investigations detected a Lyssavirus type previously identified only in fruit bats. This appears to be the first human case of encephalitis due to this Lyssavirus type.

Adult↗
PubMed1994

Reproduction of lyssaviruses: ultrastructural composition of lyssavirus and functional aspects of pathogenesis.

Lyssaviruses are considerably adapted to neural tissue, although they can also be replicated in muscle and glandular cells. In neural tissue their reproduction takes place almost exclusively in neurons, and in the course of their dissemination they make use of the structural peculiarities of this highly differentiated cell type. The replication takes place completely in the cytoplasm, although rhabdovirus leader RNA enters the nucleus and by blocking host DNA and RNA synthesis promotes viral synthetic processes. In the cytoplasm the two phases of viral reproduction, the synthesis of nucleocapsids and the formation of the envelope together with the assembly of the virion, are separate in time and space. By this separation the transmission of infection by the incomplete form of the virus, i.e., by the synaptic transfer of ribonucleoprotein-transcriptase complexes is also possible. The formation of viral envelope and assembly of full viruses on the cisternal system of the host neurons is a highly complex process, as presented here in a three-dimensional analysis. Due to the high complexity of virus assembly, defects in construction are frequent, accounting for the high yield of defective interfering particles in the course of the reproduction of lyssaviruses.

Adsorption↗
PubMed2001

Host switching in Lyssavirus history from the Chiroptera to the Carnivora orders.

Lyssaviruses are unsegmented RNA viruses causing rabies. Their vectors belong to the Carnivora and Chiroptera orders. We studied 36 carnivoran and 17 chiropteran lyssaviruses representing the main genotypes and variants. We compared their genes encoding the surface glycoprotein, which is responsible for receptor recognition and membrane fusion. The glycoprotein is the main protecting antigen and bears virulence determinants. Point mutation is the main force in lyssavirus evolution, as Sawyer's test and phylogenetic analysis showed no evidence of recombination. Tests of neutrality indicated a neutral model of evolution, also supported by globally high ratios of synonymous substitutions (d(S)) to nonsynonymous substitutions (d(N)) (>7). Relative-rate tests suggested similar rates of evolution for all lyssavirus lineages. Therefore, the absence of recombination and similar evolutionary rates make phylogeny-based conclusions reliable. Phylogenetic reconstruction strongly supported the hypothesis that host switching occurred in the history of lyssaviruses. Indeed, lyssaviruses evolved in chiropters long before the emergence of carnivoran rabies, very likely following spillovers from bats. Using dated isolates, the average rate of evolution was estimated to be roughly 4.3 x 10(-4) d(S)/site/year. Consequently, the emergence of carnivoran rabies from chiropteran lyssaviruses was determined to have occurred 888 to 1,459 years ago. Glycoprotein segments accumulating more d(N) than d(S) were distinctly detected in carnivoran and chiropteran lyssaviruses. They may have contributed to the adaptation of the virus to the two distinct mammal orders. In carnivoran lyssaviruses they overlapped the main antigenic sites, II and III, whereas in chiropteran lyssaviruses they were located in regions of unknown functions.

Adaptation, Physiological↗
PubMed1993

Protective activity of a murine monoclonal antibody against European bat lyssavirus 1 (EBL1) infection in mice.

A mouse model was designed to test in vivo the efficacy of rabies immune globulins and specific neutralizing monoclonal antibodies to prevent European bat lyssavirus 1 infection. Human or equine rabies immune globulins previously found to contain variable amounts of neutralizing bat lyssavirus crossreactive antibodies were passively transferred to mice receiving intramuscularly a lethal dose of bat lyssavirus type 1. Immune globulins did not protect mice well against bat lyssavirus 1 whereas they reduced the mortality caused by rabies virus. In contrast, mice inoculated with bat lyssavirus 1 or rabies virus survived when passively immunized with bat lyssavirus 1 specific monoclonal antibody (mAb 8-2). This monoclonal antibody, an IgG2 alpha, recognized an epitope located in the antigenic site IIa of rabies glycoprotein. A mutation replacing the lysine 198 by glutamate in a rabies variant abrogated sensitivity to this neutralizing antibody. Because of its broad neutralizing spectrum against wild virus isolates, including European bat lyssaviruses, this monoclonal antibody should be a good candidate for rabies immune globulin replacement. It could improve efficacy of rabies vaccination, used either alone or in conjunction with human rabies immune globulins or monoclonal antibody cocktail to supplement their lack of crossreactivity to European bat lyssavirus 1.

Animals↗
PubMed1998

DNA-based immunization for exploring the enlargement of immunological cross-reactivity against the lyssaviruses.

DNA-based immunization was used for studying the cross-reactivity of lyssavirus neutralizing antibodies and for exploring the induction of a wider range of protection against lyssaviruses. In order to immunize mice with homogeneous and chimeric genes of glycoproteins (G) from two divergent lyssaviruses, we used for the first time a new plasmid (pCI-neo) known to be a highly efficient vector for in vitro expression. The homogeneous plasmids pGPV and pGMok encoded the Pasteur virus (PV: genotype 1-GT-) and Mokola virus (Mok: GT 3) G, respectively. The chimeric pGMokPV encoded the NH2 part of GMok and the COOH part of GPV. These plasmids elicited full protection against intracerebral challenges with various lyssaviruses and a range of antigen-specific and non-specific immune responses. Virus neutralizing antibody (VNAb) levels were dose dependent and a single intramuscular (i.m.) injection of plasmids was sufficient to induce continuous high levels of VNAb. Production of antigen-specific T helper (Th), cytotoxic T cells (Tc) and non-specific natural killer cells was observed. Cross-reactivity studies showed that VNAb are obtained by immunizing with: (i) pGPV against GT 1 (classical rabies), GT 4 (Duvenhage: Duv), GT 5 (European Bat Lyssavirus: EBL-1) and GT 6 (European Bat Lyssavirus: EBL-2); (ii) pGMok against GT 2 (Lagos Bat: LB) and GT 3 (Mokola: Mok); (iii) pGMokPV against all GTs except GT 4 which is weakly neutralized. Therefore, the DNA-based immunization with the chimeric pGMokPV, could be very interesting to enlarge protection to all the lyssaviruses. According to the cross-reactivity of VNAb induced by the G genes, the lyssavirus GTs could be classified into two groups: the first including GT 1, 4, 5 and 6; the second including GT 2 and 3.

Animals↗
PubMed2000

Characterisation of a recently isolated lyssavirus in frugivorous zoo bats.

In July 1997 a lyssavirus was isolated in Denmark from a colony of Egyptian flying foxes (Rousettus aegyptiacus) originating from a Dutch zoo. Sequencing of a 400 nucleotides coding region of the nucleoprotein and of a major part of the G-protein ectodomain encoding region of the newly isolated virus, revealed a very high similarity with European Bat Lyssavirus subtype 1a (EBL-1a). For characterisation of the recently isolated lyssavirus in frugivorous zoo bats, 16 frugivorous bats (Rousettus aegyptiacus) of the same colony and 80 mice were experimentally infected with the Rousettus isolate or with a well defined EBL-1a strain isolated from a Dutch insectivorous bat (Eptesicus serotinus). Inoculation viruses were titrated in mice to determine LD50's of both isolates. Clinical signs of inoculated bats were recorded during 6 weeks. After showing neurological signs or at the end of the experimental infection all animals were euthanized. During the experimental infection sera and various tissues of inoculated bats were collected. Immunoassays, mouse inoculation tests (MIT) and polymerase chain reaction (PCR) were employed for detection of lyssavirus specific antibodies, antigen or RNA. Five bats inoculated with the Rousettus isolate and 2 bats inoculated with the Eptesicus isolate showed neurological signs. The remaining 9 bats survived and cleared the virus; at least under the detection limit of the used assays. Despite a much higher pathogenicity of the Rousettus isolate observed in mice, LD25's in bats were quite the same for the 2 isolates. The pathogenicity of both isolates suggested that like many other mammals, Rousettus aegyptiacus bats could be victims of lyssavirus infection besides reservoir hosts of infectious EBL1a. There was no significant difference in detecting the different lyssavirus isolates in Rousettus aegyptiacus bats. An employed immunoperoxidase staining (IP) method was very useful for sensitive detection and localization of lyssavirus antigen in histologic preparates.

Animals↗
PubMed1999

Lyssavirus glycoproteins expressing immunologically potent foreign B cell and cytotoxic T lymphocyte epitopes as prototypes for multivalent vaccines.

Truncated and chimeric lyssavirus glycoprotein (G) genes were used to carry and express non-lyssavirus B and T cell epitopes for DNA-based immunization of mice, with the aim of developing a multivalent vaccine prototype. Truncated G (GPVIII) was composed of the C-terminal half (aa 253-503) of the Pasteur rabies virus (PV: genotype 1) G containing antigenic site III and the transmembrane and cytoplasmic domains. The chimeric G (GEBL1-PV) was composed of the N-terminal half (aa 1-250) of the European bat lyssavirus 1 (genotype 5) G containing antigenic site II linked to GPVIII. Antigenic sites II and III are involved in the induction of virus-neutralizing antibodies. The B cell epitope was the C3 neutralization epitope of the poliovirus type 1 capsid VP1 protein. The T cell epitope was the H2d MHC I-restricted epitope of the nucleoprotein of lymphocytic choriomeningitis virus (LCMV) involved in the induction of both cytotoxic T cell (CTL) production and protection against LCMV. Truncated G carrying foreign epitopes induced weak antibody production against rabies and polio viruses and provided weak protection against LCMV. In contrast, the chimeric plasmid containing various combinations of B and CTL epitopes elicited simultaneous immunological responses against both parental lyssaviruses and poliovirus and provided good protection against LCMV. The level of humoral and cellular immune responses depended on the order of the foreign epitopes inserted. Our results demonstrate that chimeric lyssavirus glycoproteins can be used not only to broaden the spectrum of protection against lyssaviruses, but also to express foreign B and CTL epitopes. The potential usefulness of chimeric lyssavirus glycoproteins for the development of multivalent vaccines against animal diseases and zoonoses, including rabies, is discussed.

Amino Acid Sequence↗
PubMed2004

Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation.

Lyssaviruses, which are members of the Rhabdoviridae family, induce apoptosis, which plays an important role in the neuropathogenesis of rabies. However, the mechanisms by which these viruses mediate neuronal apoptosis have not been elucidated. Here we demonstrate that the early induction of apoptosis in a model of lyssavirus-infected neuroblastoma cells involves a TRAIL-dependent pathway requiring the activation of caspase-8 but not of caspase-9 or caspase-10. The activation of caspase-8 results in the activation of caspase-3 and caspase-6, as shown by an increase in the cleavage of the specific caspase substrate in lyssavirus-infected cells. However, neither caspase-1 nor caspase-2 activity was detected during the early phase of infection. Lyssavirus-mediated cell death involves an interaction between TRAIL receptors and TRAIL, as demonstrated by experiments using neutralizing antibodies and soluble decoy TRAIL-R1/R2 receptors. We also demonstrated that the decapsidation and replication of lyssavirus are essential for inducing apoptosis, as supported by UV inactivation, cycloheximide treatment, and the use of bafilomycin A1 to inhibit endosomal acidification. Transfection of cells with the matrix protein induced apoptosis using pathways similar to those described in the context of viral infection. Furthermore, our data suggest that the matrix protein of lyssaviruses plays a major role in the early induction of TRAIL-mediated apoptosis by the release of a soluble, active form of TRAIL. In our model, Fas ligand (CD95L) appears to play a limited role in lyssavirus-mediated neuroblastoma cell death. Similarly, tumor necrosis factor alpha does not appear to play an important role.

Animals↗
PubMedDate not supplied

The antigen-specific cell-mediated immune response in mice is suppressed by infection with pathogenic lyssaviruses.

Responsiveness of T cells (RTC) was studied in BALB/c mice intramuscularly infected with various lyssaviruses. After infection by this peripheral route, two types of viruses could be classified according to their effects: 1) pathogenic viruses, including fixed rabies Pasteur virus (serogenotype 1) and wild viruses belonging to serogenotype 1 (from a rabid fox in France and from a cow infected by a vampire bat in Brazil) or to serogenotype 5 (European bat lyssavirus 1); and 2) non-pathogenic viruses, including Mokola virus (serogenotype 3). RTC was tested by analysing in vitro the capacity of splenic T cells from infected BALB/c mice to produce cytokines after antigenic (purified lyssavirus antigens) or polyclonal stimulation (concanavalin A). Cytokine production was followed by assaying the biological activity of interleukin-2 and by testing for interleukin-2, interleukin-4 and interferon-gamma (IL2, IL4 and IFN gamma ) messenger RNAs (mRNA) by transcription into complementary DNA and amplification by the polymerase chain reaction. The initial biologically active IL2 and cytokine mRNA production was observed in mice infected with pathogenic or non-pathogenic lyssaviruses. Only mice with symptoms (infected with pathogenic viruses) lost the capacity to produce cytokines in vitro after antigen-specific stimulation. No such loss was observed after polyclonal stimulation. In mice peripherally infected with non-pathogenic viruses, no loss was observed after stimulation with lyssavirus antigens. Thus, infection with pathogenic lyssaviruses by the peripheral route induces in BALB/c mice a loss of T-cell responsiveness after antigen activation, but not after polyclonal activation.

Animals↗
PubMed1998

Characterisation of a novel lyssavirus isolated from Pteropid bats in Australia.

A novel lyssavirus isolated from Pteropid bats in Australia (Australian Bat Lyssavirus, ABLV) has been characterised using gene sequence analyses, electron microscopy and a panel of monoclonal antibodies. Electron microscopic examination of Pteropid bat and mouse brain material as well as virus isolated from tissue culture medium, showed the presence of bullet-shaped rhabdovirus particles and structures characteristic of lyssavirus. Analysis using nucleocapsid (N) specific monoclonal antibodies, showed a strong relationship between this new lyssavirus and serotype 1 rabies. The nucleotide sequence of the prototype strain of ABLV was determined from the initiator methionine codon for the nucleocapsid protein (N protein) to the amino terminus of the polymerase gene (L protein), a distance of 5344 nucleotides. Comparisons of the deduced N, phosphoprotein (P), matrix protein (M), and glycoprotein (G) proteins showed that ABLV was more closely related to serotype 1 classic rabies viruses than to other members of the Lyssavirus genus. The percent relatedness of the ABLV proteins when compared to the cognate proteins of PV (Pasteur vaccine strain) rabies was 92, 75, 87 and 75% for the N, P, M and G proteins, respectively. Phylogenetic studies of N protein sequences showed clearly that ABLV is an unrecognised member of the Lyssavirus genus and represents a new genotype, genotype 7.

Amino Acid Sequence↗
PubMed2003

New lyssavirus genotype from the Lesser Mouse-eared Bat (Myotis blythi), Kyrghyzstan.

The Aravan virus was isolated from a Lesser Mouse-eared Bat (Myotis blythi) in the Osh region of Kyrghyzstan, central Asia, in 1991. We determined the complete sequence of the nucleoprotein (N) gene and compared it with those of 26 representative lyssaviruses obtained from databases. The Aravan virus was distinguished from seven distinct genotypes on the basis of nucleotide and amino acid identity. Phylogenetic analysis based on both nucleotide and amino acid sequences showed that the Aravan virus was more closely related to genotypes 4, 5, and--to a lesser extent--6, which circulates among insectivorus bats in Europe and Africa. The Aravan virus does not belong to any of the seven known genotypes of lyssaviruses, namely, rabies, Lagos bat, Mokola, and Duvenhage viruses and European bat lyssavirus 1, European bat lyssavirus 2, and Australian bat lyssavirus. Based on these data, we propose a new genotype for the Lyssavirus genus.

Animals↗
PubMed2001

Interaction of lyssaviruses with the low-affinity nerve-growth factor receptor p75NTR.

The low-affinity nerve-growth factor receptor p75NTR interacts in vitro with the rabies virus (RV) glycoprotein and serves as a receptor for RV. The Lyssavirus genus comprises seven genotypes (GTs) of rabies and rabies-related viruses. The ability of p75NTR to interact with the glycoprotein of representative lyssaviruses from each GT was investigated. This investigation was based on a specific binding assay between BSR cells infected with a lyssavirus and Spodoptera frugiperda (Sf21) cells expressing p75NTR on the cell surface. A specific interaction was observed with the glycoprotein of GT 1 RV (challenge virus standard or Pasteur virus strains) as well as wild-type RV and the glycoprotein of GT 6 European bat lyssavirus type 2. In contrast, no interaction was detected with the glycoprotein of lyssaviruses of GTs 2-5 and 7. Therefore, p75NTR is only a receptor for some lyssavirus glycoproteins, indicating that the other GTs must use an alternative specific receptor.

Animals↗
PubMed2002

Sequence analysis of an isolate from a fatal human infection of Australian bat lyssavirus.

Australian bat lyssavirus (ABLV), which occurs in pteropid and insectivorous bat populations, causes a rabies-like encephalitis in infected humans. We report the first complete sequence of an ABLV isolate obtained from a human who developed symptoms 27 months after being bitten by an infected flying fox. This isolate is the smallest lyssavirus to be sequenced, with a size of 11,918 nucleotides. Analyses of previously unsequenced regions and the complete genome confirm its close relationship with classical rabies viruses. In addition, a leucine zipper-like motif, not present in the other lyssaviruses, was found in the conserved domain I of the polymerase protein. This is the first report of a lyssavirus to vary in an 11-nucleotide, strictly conserved, complementary terminal sequence. This region is thought to encode important cis-acting regulatory signals; ABLV variation indicates a greater degree of flexibility than was thought for lyssaviruses in this region. A comparison of the pteropid and insectivorous isolates of ABLV indicates considerable differences between the two viruses. If the divergence of the two occurred on the Australian mainland, ABLV may have been endemic to Australia well before European colonisation.

Adult↗
PubMed2003

Cross-reactive antigenicity of nucleoproteins of lyssaviruses recognized by a monospecific antirabies virus nucleoprotein antiserum on paraffin sections of formalin-fixed tissues.

Diagnosis of rabies is routinely confirmed by detection of rabies virus antigens in acetone-fixed frozen brain tissues or imprint smears using an immunofluorescence method with commercial antirabies virus antibodies. Since recent molecular analyses disclosed wide heterogeneity in the genome sequences of rabies virus strains and related lyssaviruses, it is necessary to confirm the presence of common epitopes in these lyssaviruses. In this study we confirmed the presence of cross-reactive antigens of various lyssaviruses in paraffin sections of formalin-fixed tissue using a monospecific rabbit antiserum prepared by immunization with a recombinant nucleoprotein of rabies virus. By immunohistochemical application, the antigen was detected predominantly in the cytoplasm of neurons in the brains of mice infected with rabies virus, Duvenhage virus, Mokola virus and European bat lyssavirus-1, while no cross-reaction was observed in uninfected humans and animals including dogs, bats, and raccoons. In addition, we examined one autopsy case that was infected in a rabies-endemic nation and developed the clinical manifestation of rabies after returning to Japan in 1970, and found that the antigen was well preserved in paraffin sections of formalin-fixed tissues. Thus, this suggests that the lyssavirus-specific antigen is recognized by the monospecific antibody against rabies virus nucleoprotein, and that this cross-reactive antigen is detectable on formalin-fixed paraffin-embedded tissues by immunohistochemical analysis.

Amino Acid Sequence↗
PubMed2003

A molecular epidemiological study of Australian bat lyssavirus.

The genetic diversity of Australian bat lyssavirus (ABL) was investigated by comparing 24 ABL isolate glycoprotein (G) gene nucleotide sequences with those of 37 lyssaviruses representing Lyssavirus genotypes 1-6. Phylogenetic analyses indicated that ABL forms a monophyletic group separate from other lyssaviruses. This group differentiates into two clades: one associated with Pteropus (flying fox) species, the other with the insectivorous bat Saccolaimus flaviventris. Calculation of percentage nucleotide identities between isolates of the two clades revealed up to 18.7 % nucleotide sequence divergence between the two ABL variants. These observations suggest that ABL is a separate lyssavirus species with a similar epidemiology to chiropteran rabies virus (RV), where two distinct ABL variants co-exist in Australia in bat species with dissimilar ecology. Analyses of selection pressures in ABL G gene sequences provided some evidence of weak positive selection within the endodomain at amino acids 499 and 501, although in general the dominant evolutionary process observed was purifying selection. This intimates that, in nature, isolates of ABL, like those of RV, are subject to relatively strong selective constraints, suggesting a stability of host species, cell tropisms and ecological conditions.

Amino Acid Sequence↗
PubMed1999

A retrospective search for lyssavirus in humans in the Northern Territory.

BACKGROUND: Following the 1996 discovery of a rabies-like lyssavirus in Australian flying foxes, it was unclear whether this was a new epizootic or an unrecognised, previously existing disease. OBJECTIVE: To review cases of unexplained encephalitis in the Northern Territory (NT) to test available clinical specimens for lyssavirus and survey the use of diagnostic tests by clinicians. METHODS: The NT hospital morbidity database was searched from January 1992 to September 1996 for all Royal Darwin Hospital (RDH) cases with an ICD-9 code encompassing encephalitis or viral meningitis. Final diagnoses were determined by hospital record review. For cases of unexplained encephalitis, we assessed the use of diagnostic tests and located clinical specimens for testing for lyssavirus-specific inclusion bodies via immunohistochemistry, immunofluorescence and reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Encephalitis occurred in 34/154 (22%) cases located by the search; 53% (18/34) of encephalitis cases were unexplained. Of these, 24% had no serology performed and 47% had no blood cultures taken. Four (22%) died and two had autopsies. These were the only two cases with clinical specimens available for testing. They were negative for lyssavirus. None of the 71 cases coded as viral meningitis had unexplained encephalitis. CONCLUSION: There was a considerable proportion of unexplained illness among NT cases of encephalitis. IMPLICATIONS: Clinicians should test for lyssavirus in patients with encephalitic symptoms and a postmortem should be sought where death is unexplained. Specimens should be stored to enable testing for emerging infectious diseases.

Diagnosis, Differential↗
PubMed2001

Screening of active lyssavirus infection in wild bat populations by viral RNA detection on oropharyngeal swabs.

Brain analysis cannot be used for the investigation of active lyssavirus infection in healthy bats because most bat species are protected by conservation directives. Consequently, serology remains the only tool for performing virological studies on natural bat populations; however, the presence of antibodies merely reflects past exposure to the virus and is not a valid marker of active infection. This work describes a new nested reverse transcription (RT)-PCR technique specifically designed for the detection of the European bat virus 1 on oropharyngeal swabs obtained from bats but also able to amplify RNA from the remaining rabies-related lyssaviruses in brain samples. The technique was successfully used for surveillance of a serotine bat (Eptesicus serotinus) colony involved in a case of human exposure, in which 15 out of 71 oropharyngeal swabs were positive. Lyssavirus infection was detected on 13 oropharyngeal swabs but in only 5 brains out of the 34 animals from which simultaneous brain and oropharyngeal samples had been taken. The lyssavirus involved could be rapidly identified by automatic sequencing of the RT-PCR products obtained from 14 brains and three bat oropharyngeal swabs. In conclusion, RT-PCR using oropharyngeal swabs will permit screening of wild bat populations for active lyssavirus infection, for research or epidemiological purposes, in line not only with conservation policies but also in a more efficient manner than classical detection techniques used on the brain.

Animals↗
PubMed2002

Serologic evidence of Lyssavirus infections among bats, the Philippines.

Active surveillance for lyssaviruses was conducted among populations of bats in the Philippines. The presence of past or current Lyssavirus infection was determined by use of direct fluorescent antibody assays on bat brains and virus neutralization assays on bat sera. Although no bats were found to have active infection with a Lyssavirus, 22 had evidence of neutralizing antibody against the Australian bat lyssavirus (ABLV). Seropositivity was statistically associated with one species of bat, Miniopterus schreibersi. Results from the virus neutralization assays are consistent with the presence in the Philippines of a naturally occurring Lyssavirus related to ABLV.

Animals↗