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Antibodies against canine distemper virus were determined before and after the administration of a live canine distemper virus vaccine to 16 wild dogs Lycaon pictus. Antibody levels were either very low or non-detectable. The results were inconclusive.
Serum and cerebrospinal fluid (CSF) measles and distemper antibody levels were quantified in a series of twenty patients (four subacute sclerosing panencephalitis (SSPE); ten multiple sclerosis (MS); six non-MS neurological cases) using independent competitive inhibition radioimmunoassays. These results were used in a Tourtellotte calculation to measure the intracerebral IgG synthesis to each virus. The results confirmed that in SSPE there is a greatly enhanced intracerebral measles antibody synthesis (6.0 mg/day). However, it was found that in SSPE this represents only part of a general systemic measles hyperimmunization as the intracerebral measles antibody synthesis relative to the total body measles synthesis was not significantly different from other groups (8%); In MS patients there was increased intracerebral immunoglobulin synthesis but the measles antibody levels were neither significantly elevated nor different from the control group. No evidence was found to support the concept that canine distemper virus is implicated in either MS or SSPE.
A 16-week-old dog developed distemper 3 weeks after the 2nd of 2 vaccinations for canine distemper (CD). Symptomatic treatment was without effect and the dog was euthanatized. Prior to euthanasia, a blood sample was obtained for serologic study. The dog was found to be hypogammaglobulinemic and to have a serum-neutralization antibody titer of 1:16 to CD virus, which is considerably lower than the average 28-day response to a single CD vaccination (1:312). Histologic examination revealed absence of germinal centers in spleen and lymph nodes, generalized lymphoid depletion, and thymic hypoplasia. Comparison with primary immunodeficiencies of man and domestic animals and with CD virus-induced immune suppression led to inconclusive interpretation of these data. Thorough immune function analysis was deemed mandatory for separating primary immunodeficiency from CD virus-induced immunosuppression in dogs.
Two outbreaks of an encephalitis apparently induced by an attenuated live distemper vaccine occurred in a large ferret breeding establishment in New Zealand. Approximately 350 of 6,000 young ferrets 16-22 weeks old died. Many were found dead with no premonitory signs, others showed severe neurological signs. Some with central nervous system (C.N.S.) signs recovered. Pathological examination showed no gross abnormalities except for a few with mild conjunctivitis, rhinitis and lung emphysema. Microscopically there was a moderate to massive non-inflammatory necrosis of hippocampal nerve cell bodies. In those animals which survived for several days with CNS signs there was also a mild to moderately severe non-supportive encephalitis, and in some of these distinct neuronal intranuclear and intracytoplasmic eosinophilic inclusion bodies were seen. Some ferrets also had a bronchiolitis with intracytoplasmic eosinophilic inclusion bodies in bronchiolar epithelium. All these lesions suggest that a distemper like condition was involved. About half of the ferrets also had a mild to severe inflammatory myocardial necrosis.
The amino acid composition of the two surface proteins of the recently isolated morbillivirus phocid distemper virus (PDV) were deduced from the nucleotide sequence. The fusion (F) protein of PDV exhibited characteristics similar to those of other morbillivirus F proteins. The overall amino acid similarity with its closest homologue, canine distemper virus (CDV), was 72%. From the context of the starting codons and the requirement for a hydrophobic signal peptide, it is likely that translation of the PDV F mRNA starts at the third AUG, corresponding to codon 95 in the long open reading frame of the PDV F gene. After removal of the signal peptide, F0 starts at amino acid 105. From this position the F protein of PDV and CDV exhibit 84% amino acid similarity. The PDV haemagglutinin (H) protein showed 74% amino acid similarity with CDV H protein and highly conserved features responsible for the tertiary structure. Despite these similarities, the two H proteins show marked antigenic differences when probed with monoclonal antibodies. Earlier studies have indicated that rinderpest virus (RPV) is the prototype virus of the morbillivirus genus, from which first CDV/PDV and later measles virus (MV) evolved. From the close relationship shown in this study, it is likely that the divergence of CDV and PDV occurred after MV evolved from RPV.
The nucleotide and deduced amino acid sequences of two genes of phocid distemper virus (PDV) were determined by cDNA cloning and sequencing. The long open reading frame of the gene encoding the nucleocapsid (N) protein is presented. As with other morbilliviruses, the phosphoprotein (P) gene of PDV was found to be located after the 5' end of the N gene and before the 3' end of the matrix protein gene. The P gene was shown to have the capacity to encode three distinct proteins, P, V and C, in analogy to other morbilliviruses. The results presented provide evidence for editing of the PDV P mRNA transcript by insertion of G residues. When the nucleotide and deduced amino acid sequences of the N, P, V and C genes were aligned with corresponding sequences of other established members of the morbillivirus genus, compelling homology was found between PDV and canine distemper virus (CDV), whereas there was markedly less similarity between PDV and measles virus or rinderpest virus. On the basis of the alignments presented, the estimated amino acid sequence similarity between the N and P genes of PDV and CDV was 84% and 76%, respectively. These differences at the genomic level indicate that the viruses are two separate entities.
The nucleotide sequences of the phosphoprotein (P)/V/C and matrix (M) protein genes of phocine distemper virus (PDV) have been determined and the deduced amino acid sequences of the proteins derived from these genes compared with those of the other morbilliviruses. The 1655 nucleotides of the P gene encode a phosphoprotein of 507 amino acid residues (from nucleotide numbers 60 to 1583) which is 75% identical to that of canine distemper virus (CDV). The C proteins of the two viruses are 73% identical. The C protein has the same length, 174 amino acid residues, as C of CDV. The nucleotide sequences of the P genes are 78% identical. The editing site in the P gene is present as a stretch of 18 nucleotides, conserved in all other morbilliviruses. A V-like protein can be accessed by insertion of one G residue at this site. The P and M genes are separated from adjacent genes and each other by the CTT trinucleotide sequence which is totally conserved in morbilliviruses. The M gene is 1447 nucleotides long and encodes a typical paramyxovirus M protein of 335 amino acids (identical in length to those of CDV, measles virus and rinderpest virus). The gene is 78% identical to CDV in the coding region (nucleotides 32 to 1039) but only 34% identical to CDV in the 407 nucleotides of the 3' untranslated sequence of the M mRNA. The M protein of PDV is 91% identical to the M protein of CDV. The data demonstrate interesting variations in the level of conservation of various genome areas and prove the distinct nature of PDV.
Eight harbour seals (Phoca vitulina), two of them seronegative, six seropositive against PDV and a seronegative grey seal (Halichoerus grypus) were exposed to a low doses of a cell culture-propagated phocine distemper virus isolate (PDV 2558/Han 88). An intranasal route of inoculation was chosen. Clinical signs, resembling those of 1988's seal disease and seroconversion were observed in both seronegative harbour seals. One of them succumbed to the infection. The virus was not transmitted to another susceptible harbour seal which served as in-contact animal. Virus could be recovered from leucocytes of the diseased seals. Viremia was also present in a seropositive harbour seal that developed mild clinical signs; other seropositive seals were protected from clinical disease. The grey seal showed seroconversion upon inoculation, but did not develop any signs of disease. The humoral immune response of the seals plainly discriminated between homologous (PDV) and heterologous (canine distemper virus, CDV) virus as shown by virus neutralization tests and an antibody-binding assay (PLA).
The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human disease. Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin-6 and c-FOS production, possibly via the transcription factor NF-kappa B.
Canine Distemper Virus (CDV) produces an encephalitis in dogs that varies with viral strain. We have studied the cell tropisms of two virulent strains (CDV-SH and CDV A75-17) and an attenuated strain, Rockborn (CDV-RO), in cultured canine brain cells. Infected cell types were identified by double immunofluorescent labeling of specific cell markers and viral antigens. All viral strains studied produced infection in astrocytes, fibroblasts, and macrophages. Neurons were not infected by CDV A75-17 but were rapidly infected by CDV-SH and CDV-RO. Multipolar oligodendrocytes were very rarely infected by any of the virus strains. In contrast, a morphologically distinct subset of bipolar oligodendrocytes were commonly infected by CDV-SH and CDV-RO. The kinetics of infection in the astrocytes, oligodendrocytes, neurons, and macrophages varied between strains. Both CDV-SH and CDV-RO rapidly infected bipolar oligodendrocytes, astrocytes, neurons, and macrophages by 14 days post infection while infection by CDV A75-17 was delayed until after 28-35 days post infection. The differences in the growth kinetics and cell tropisms for some brain cells, exhibited by the three viral strains examined in this in vitro study, may relate to the different CNS symptoms that these strains produce in vivo.
In vitro studies on glial cell changes in canine distemper virus (CDV) infection could be useful for the understanding of the pathogenesis of demyelination in vivo in this disease. Mixed glial cell cultures derived from neonatal mice and dogs were infected with CDV and examined using immunocytochemical techniques demonstrating specific oligodendroglial and astroglial cell markers. Astrocytic changes were similar in both murine and canine cultures and consisted of loss of processes, cell fusion, and cell necrosis. Marked oligodendroglial lesions were apparent in the canine brain cultures and were characterized by focal perikaryal protrusions, swelling and loss of cell processes, and cell necrosis. Fusion between oligodendrocytes was not observed. Fusion between astrocytes and oligodendrocytes could not be documented with double labeling techniques. In contrast to the canine cultures, murine oligodendrocytes remained relatively unaffected by the infection. These findings were discussed with respect to cell pathology and mechanisms of demyelination in vivo. The exact nature of the canine oligodendroglial lesions in vitro needs to be studied in further experiments.
Experimental infection of gnotobiotic Beagle dogs with neurovirulent R252 canine distemper virus (CDV) resulted in hematogenous dissemination of virus to the central nervous system (CNS). Viral antigen was first detected within CNS capillary and venular endothelia and/or perivascular astrocytic foot processes and pericytes. The number of primary infection sites was evenly distributed throughout the neuraxis. Leukocytic infiltrations followed CNS endothelial cell infection by 1-2 days and were composed of both viral antigen-positive and -negative cells. These results indicate that CDV infection of the CNS is initiated by the interaction of circulating infectious virus with endothelial cells.
Dog brain cell cultures were infected with different canine distemper virus (CDV) strains to study the oligodendrocytes, which were characterized with eight different antibodies to cover the whole oligodendroglial population in the culture. A few weeks after infection all oligodendroglial cell types started to degenerate and disappeared from the culture. However, since no CDV protein could be demonstrated in the degenerating oligodendrocytes with extensive double-labelling studies, this lesion can not be explained as being a result of cytolytic infection. This conclusion was further supported in experiments with plaque-forming CDV, in which viral replication is restricted to the cytolytic areas only; oligodendrocytes also degenerated in virus-free areas between the plaques. The hypothesis of toxic factors released by other infected cell types in the culture leading to secondary damage of the oligodendrocyte could not be confirmed by transferring supernatants from infected to normal cultures. Whereas the presence of toxic factors can not be completely excluded, the possibility of an abortive infection of the oligodendrocytes with no or very limited viral protein synthesis is discussed.
Acute canine distemper virus (CDV)-induced demyelinating lesions were examined with double-labelling immunocytochemistry simultaneously demonstrating CDV antigen and glial fibrillary acidid protein (GFAP) as marker for astrocytes. It was shown that 64% of all astrocytes within the demyelinating lesions were infected and that 95% of all infected cells counted in the lesions were astrocytes. These results suggest that the astrocyte is the main target for CDV and that astroglial infection may play an important role in the mechanism of demyelination.
Formalin-fixed brain tissues from 16 dogs with naturally occurring canine distemper virus (CDV) infection were investigated immunohistochemically by a panel of eight monoclonal antibodies (mAb) directed against four structural CDV proteins. Three mAb recognizing different epitopes of the polymerase (P-1, P-2, P-3) protein, two clones identifying different epitopes on each, the nucleocapsid (NP-1, NP-2) and fusion (F-2, F-3) protein, and one mAb directed against the hemagglutinin (H-2) protein were used. The immunoreactivity of the clones was tested on formalin-fixed, paraffin-embedded Vero cells, which were lytically infected with the neurotropic R252 (R252-CDV) or the Onderstepoort (CDV/Ond) strain of CDV. Clones directed against the H-2 and F-3 epitope recognized CDV/Ond but not R252-CDV. The remaining six clones showed positive immunoreaction with both CDV strains. In vivo expression and distribution of the individual proteins and their epitopes varied substantially between animals and within lesions from the same animal. The NP-2 epitope showed positive immunostaining in all 16 cases. The P-2 epitope was demonstrated in 13, the NP-1 epitope in 12, the P-3 epitope in 9, and the P-1 epitope in 3 brains, but staining was severely reduced compared with the NP-2 epitope and restricted to areas with strong NP-2 expression. Immunostaining was prominent in early and subacute and reduced in chronic demyelinating lesions. mAb directed against the H and F protein showed no immunoreaction in diseased brains.
The small plaque virus (SPV), derived from the Onderstepoort strain of canine distemper virus (CDV) does not cause a lethal encephalitis in weanling hamsters. When we immunosuppressed hamsters infected with this virus they developed an acute disease, similar to that produced by the large plaque virus (LPV). Passive transfer of maternal antibody from SPV infected mothers to their offspring was effective in preventing acute disease following LPV infection. Co-infection of animals with both LPV and SPV resulted in increased hamster survival, associated with high titres of serum antibody. Similarly, heat inactivated SPV, present during infection with LPV, increased the survival rate. Heat inactivated LPV did not inhibit acute disease, although hamsters had high titres of neutralizing antibody. A small number of animals developed a delayed or recurring paralysis after immunosuppression, exposure to maternal antibody or co-infection. It would appear that the neurovirulence of CDV for hamsters can be modified by altering the levels of circulating antibody early in infection.
Persistent infection with virulent canine distemper virus (CDV-SH) was established in 2 human lymphoblastoid B cell lines (Wi-L2 and Raji), and one human (HSB), one simian (1670) and one canine (CT-45-S) lymphoblastoid T cell line. Cell free virus from persistently infected T cell lines was avirulent for dogs but virulence was maintained during 31 cell passages in persistently infected B cell lines.
Pairs of dogs were immunized with 2 injections of a) measles virus material containing hemagglutinin but no hemolysin [Tween 80 and ether (TE) treated] b) material containing both hemagglutinin and hemolysin (freeze-dried and heated at 95 degrees C for 30 minutes), and c) live measles virus. Two unimmunized dogs were used as controls. All 8 dogs were challenged with virulent canine distemper virus (CDV). The two unimmunized dogs contracted a lethal infection, whereas immunized animals only showed mild signs of infection. Preimmunization with TE treated antigen gave the weakest protection. The animals displayed fever between day 4 and 10 after challenge. All titers of preexisting antibodies were boosted and antibodies against the measles hemolysin and CDV neutralizing antibodies increased from undetectable to moderate levels. Non-infectious intact virus (b) gave a more pronounced antibody response than TE antigen but antibodies against the hemolysin could not be detected. There was a good protection against disease (limited fever response). Replication of CDV caused a raise of antibody titers to levels normally seen only under conditions of hyperimmunization. Live measles virus stimulated the production of antibodies against both envelope components, but in spite of this virulent CDV could multiply and boost the titers of all antibodies.