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Malignant catarrhal fever.

Malignant catarrhal fever is briefly reviewed and recent findings are described. Initially the disease was observed as a disease of cattle in Europe where, although no cause could be identified, circumstantial evidence implicated sheep as a source of infection and it was thus designated 'sheep-associated' malignant catarrhal fever. Subsequently the disease was observed in Africa where it became evident that a herpesvirus which normally infects wildebeest was the cause. It is now apparent that deer are highly susceptible to both forms of the disease, the sheep-associated form being a serious problem in farmed deer. The wide spectrum of clinical and pathological changes that occur in affected deer are described. A major constraint to studies of sheep-associated malignant catarrhal fever has been the absence of an experimental laboratory system. However, from affected deer it has been possible to transmit the disease to rabbits and thus has allowed detailed pathogenesis studies to be made which are summarised in this paper. It is suggested that the agent of sheep-associated malignant catarrhal fever is a virus and that when a particular subpopulation of T-lymphocytes is infected a profound immunological perturbation results; the lesions of malignant catarrhal fever being explained by a benign T-lymphocyte hyperplasia accompanied by a deregulation of cytotoxic natural killer lymphocytes that gives rise to tissue necrosis.

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Virologic studies on cattle with naturally occurring and experimentally induced malignant catarrhal fever.

Malignant catarrhal fever is an important disease of cattle and certain wild ruminants. It occurs in sporadic and epizootic forms in Colorado cattle. Specimens from 15 cattle with naturally occurring malignant catarrhal fever and 5 cattle with induced disease were examined for cell-free and cell-associated viruses. Enteroviruses were isolated from leukocytes of 2 cattle with field cases of the disease. A herpesvirus with characteristics of the "Movar"-type, isolated from the spleen of another steer with a field case could be propagated optimally in bovine fetal spleen cells. A cell-associated virus, forming polykaryons, was isolated in adrenal and thyroid cells from 3 cattle with experimentally induced malignant catarrhal fever. It was cultured from leukocytes, ependymal tissue, spleen, lymph node, kidney and thyroid and adrenal glands of affected cattle and remained cell-associated in 48 subsequent passages. It was inactivated by freezing and thawing and by treatment with ultrasound; its polykaryon-forming activity was inhibited by 25 mug of 5 fluoro-2' deoxyuridine/ml. This viral agent replicated in bovine fetal adrenal, thyroid, and spleen cells, but not in primary kidney cells or in MDBK, HeLa, or L cells. A representative isolate was identified electronmicroscopically as an enveloped virus, 120 to 150 nm in diameter. Structural analysis indicated that it had properties of the bovine syncytial viruses. Attempts to induce MCF in cattle with 1 of the isolates failed. A parvovirus was isolated from the jejunal lymph node of calf 72-P-293, which had the experimentally induced disease and was also infected with the syncytial virus.

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Antibody to alcelaphine herpesvirus-1 (AHV-1) in hamsters experimentally infected with AHV-1 and the 'sheep-associated' agent of malignant catarrhal fever.

Malignant catarrhal fever was induced in four groups of hamsters by the inoculation of cells infected with either the C/500 isolate of alcelaphine herpes-virus-1 (AHV-1) or the sheep-associated agent derived from cattle, red deer or Père David's deer. Using an indirect immunofluorescence assay, antibody to AHV-1 was detected in sera of clinically affected animals of all four groups. The reaction of sera from hamsters affected with malignant catarrhal fever induced by AHV-1 caused diffuse cytoplasmic staining while that from sera of hamsters with the sheep-associated form of the disease stained particulate nuclear antigens. Tests employing three other bovid herpesviruses were negative and no reaction was found with sera from normal hamsters. These studies provide convincing evidence that a virus antigenically related to AHV-1 is the cause of sheep-associated malignant catarrhal fever and that the same virus probably causes this form of the disease in both cattle and deer.

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Malignant catarrhal fever. I. Response of American cattle to malignant catarrhal virus isolated in Kenya.

Fifty-three American cattle were inoculated with malignant catarrhal fever virus isolated from a wildebeest in Kenya. Three animals showed the mild form of the disease and recovered, and 47 showed the severe form of the disease. The other three did not react. Of the 47 cattle, 28 died, 16 were killed for the collection of specimens and three recovered. The incubation period for the 47 cattle ranged from 16 to 29 days and the course of the fatal disease for 28 cattle averaged three to 23 days. Virus titration of specimens from nine infected steers yielded a mean titer of 10(4)/TCID50 per gm for lymph nodes, 10(3) TCID50 per mL for buffy coats and 10(2.3) TCID50 per gm for spleens. Smaller amounts of virus were found in the liver, kidneys, adrenals and thyroids. Malignant catarrhal fever virus was also found in nasal secretions and saliva of viremic cattle. Viral infectivity was shown in bovine buffy coat cells stored at 4 degrees C for two days but was immediately destroyed upon freezing even when glycerine or dimethylsulfoxide was added. Viral particles were not found in infected animal tissues by electron microscopy. The disease was successfully transmitted in steers by intratracheal intubation and by aerosol inhalation but not by contact.

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Derivation of a DNA clone corresponding to the viral agent of sheep-associated malignant catarrhal fever.

Malignant catarrhal fever is a fatal lymphoproliferative and degenerative disease of ruminants. One causative agent is the gammaherpesvirus alcelaphine herpesvirus 1 (AHV-1), which produces no disease in its natural host, the wildebeest (Connochaetes species). Epidemiological evidence implicates sheep as the carrier of a similar virus. However, attempts to culture this virus from sheep or from animals affected with sheep-associated malignant catarrhal fever (SA-MCF) have failed. Lymphoblastoid cells have been propagated from cattle, deer and rabbits with SA-MCF. Although these cells show no evidence of viral particles or antigens, hybridisation experiments now show that they contain DNA sequences homologous to those of AHV-1. A genomic library was constructed from one of these lymphoblastoid cell lines and a clone identified which hybridised to cloned AHV-1 DNA. The authors believe that this clone contains part of the SA-MCF viral genome, and that the SA-MCF virus and AHV-1 are closely related gammaherpesviruses.

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Malignant catarrhal fever III. Experimental infection of sheep, domestic rabbits and laboratory animals with malignant catarrhal fever virus.

Five of 19 sheep became infected when inoculated with a virulent strain of malignant catarrhal fever virus isolated in Kenya One of the infected animals was killed in extremis; its blood and lymph node suspension reproduced the classical disease in three steers. Calves exposed to these sheep did not become infected during 89 days of close contact. The Kenya strain of malignant catarrhal fever virus infected rabbits, guinea pigs and hamsters, producing occular and nasal discharges, paralysis and death. The virus recovered from these animals in cell cultures produced disease in rabbits and steers. Neutralizing antibodies were found in the rabbit sera. Infant mice, chicken and duck embryos were refractory to infection with malignant catarrhal fever virus.

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Characterisation of the lymphoproliferation in rabbits experimentally affected with malignant catarrhal fever.

Malignant catarrhal fever (MCF) in rabbits caused by the three Herpesviruses: alcelaphine herpesvirus-1 (AHV-1), ovine herpesvirus-2 (OHV-2) and hippotragine herpesvirus-1 (HipHV-1) induced hyperplasia of lymphoid tissues and accumulations of mononuclear lymphoid cells in non-lymphoid tissues. However, certain lymph nodes were affected preferentially. The lymphoid cells in non-lymphoid tissues were CD43+ T-cells which showed evidence of in situ multiplication. A more detailed phenotypic analysis of splenocytes and lymph node cells in AHV-1 infected rabbits suggested that the hyperplasia was probably due to the expansion of CD8+ T-cells. On the basis of these data and the observations of other authors, that no or very little viral expression can be detected in lesions of MCF affected animals, we propose that the pathogenesis of MCF results from a dysregulation of a secretory T-cell activator. The variable pathology induced by the three viruses may reflect a quantitative or qualitative differences in this proposed activator.

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PCR detection of ovine herpesvirus-2 DNA in Indonesian ruminants--normal sheep and clinical cases of malignant catarrhal fever.

Malignant catarrhal fever (MCF), a fatal viral disease of cattle and other large ruminants, has a worldwide distribution. There are two forms of the disease, one of which, is caused by Alcelaphine herpesvirus-1 (AHV-1) and is derived from wildebeest. The other form is associated with domestic sheep and is caused by ovine herpesvirus-2 (OHV-2). The disease in Indonesia is sheep-associated with the preferred livestock of this area, Balinese cattle (Bos javanicus) and water buffalo (Bubalus bubalis), both highly susceptible to SA-MCF. The incidence in these species is thought to be high but the prevalence and economic losses attributable to SA-MCF have been difficult to assess. a polymerase chain reaction (PCR) test, based on a cloned OHV-2 gene sequence, was successfully applied to the detection of OHV-2 DNA in normal sheep and animals affected with SA-MCF. OHV-2 DNA was detected in eleven confirmed cases of SA-MCF and in the peripheral blood leucocyte (PBL) fraction of six latently infected sheep. These findings have confirmed that the PCR can be of value in establishing a diagnosis of MCF and that the aetiological agent of MCF in Indonesia is OHV-2. The amplification of DNA from the PBL of goats suggests that they are infected with a similar or identical herpesvirus.

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Chronic generalized obliterative arteriopathy in cattle: a sequel to sheep-associated malignant catarrhal fever.

Malignant catarrhal fever (MCF) in cattle is generally associated with a short clinical course and a high case fatality rate (90-95%). The lesions in cattle that survive acute MCF for a prolonged period or appear to recover have not been documented. In a naturally occurring outbreak of MCF in a herd of beef cattle in Wyoming, 7 of 84 yearling heifers (8.3% of replacement herd) and 2 of 230 cows (0.9% of cow herd) developed clinical signs of pyrexia, mucopurulent discharge, bilateral keratitis, and weight loss following contact with ewes that had lambed 34-62 days earlier. Six of 9 affected cattle were examined postmortem following clinical signs (CS) that developed 2-150 days earlier. Three cattle with CS for < or = 39 days had lesions of regional lymphadenopathy and widespread severe segmental lymphoid arteritis-phlebitis that were typical of acute MCF, and proliferative intimal lesions were present in a small proportion of arteries at days 20 and 39 of CS. By contrast, 3 cattle that survived to 90, 105, and 150 days after clinical onset had distinctive arterial lesions in multiple organs, characterized by proliferative concentric fibrointimal plaques, disrupted inner elastic lamina, focally atrophic tunica media, and vasculitis of variable severity. Immunohistochemical and ultrastructural examination of intimal plaques identified the predominant cellular component to be smooth muscle cells with a contractile phenotype. No viral structures were seen. Serologic studies, using a competitive inhibition enzyme-linked immunosorbent assay (CI-ELISA) that detects antibody to an epitope broadly conserved among isolates of the MCF virus, found that 2 chronically affected cattle were serologically positive between days 42 and 100 of CS, with seroconversion in 1 animal between days 52 and 73 of CS. Seroprevalence was 7.9% in the 76 remaining healthy animals of the replacement heifer herd and 40% (75% in adult sheep and 4% in lambs) in the in-contact sheep flock 77 days after onset of CS in the index case. This episode suggests that, in addition to the common and well recognized acute form of MCF in cattle, this viral infection encompasses a disease spectrum that includes chronic disease and partial to "complete" clinical recovery, and in recovered animals chronic obliterative arteriopathy is the preeminent lesion.

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Malignant catarrhal fever in cattle experimentally inoculated with a herpesvirus isolated from a case of malignant catarrhal fever in Minnesota USA.

A malignant catarrhal fever (MCF)-like syndrome was experimentally induced in three steers, which were under immunization trials with a herpesvirus previously isolated from a case of MCF in a cow in Minnesota USA. The clinical signs observed in the three steers, and the pathological and histological lesions observed in two of these steers which succumbed to the disease syndrome were indistinguishable from those described for MCF. Although seroconversion was readily demonstrated in the three animals, virus was not re-isolated from the blood leucocytes, secretions and tissues obtained from the two animals which succumbed to the syndrome during the course of the disease and after death. However, a herpesvirus which showed cell rounding cytopathic effects (cpe) in bovine thyroid cells (Bth), was re-isolated from the one steer which survived the disease.

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Role of wildebeest fetal membranes and fluids in the transmission of malignant catarrhal fever virus.

Malignant catarrhal fever virus was not isolated from samples of fetal membranes or fluid collected from 93 calving wildebeest (Connochaetes taurinus) in Kenya Maasailand. Cell-free strains of malignant catarrhal fever virus were very rapidly inactivated when exposed to the sun under field conditions, at least 3.0 log10 units/25 microliter being lost per hour at midday. It is suggested that wildebeest fetal membranes and fluids act as visual markers for areas of pasture which are particularly heavily contaminated with malignant catarrhal fever virus in oculonasal secretions of wildebeest calves. It is possible that starting to graze cattle one to two hours later each morning may be a useful measure for helping to protect cattle from malignant catarrhal fever in areas where they are forced to share pastures with calving wildebeest.

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The malignant catarrhal fever complex.

Malignant catarrhal fever (MCF) is defined as a clinicopathological syndrome caused by related herpesviruses and acquired from persistently infected wildebeest and sheep. There is convincing epidemiologic and virologic evidence that Alcelaphine herpesvirus 1 (AHV1) causes the wildebeest-derived disease (WD-MCF). Present knowledge suggests that a herpesvirus related to AHV1 may be associated with some cases of the non-wildebeest-associated disease (NWA-MCF). However, this virus possibly represents a passenger virus not related with the ultimate cause of the disease. Moreover, evidence for the role played by sheep as the reservoir for the agent of NWA-MCF is not convincing and awaits confirmation.

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Immunoblotting analysis of the reaction of wildebeest, sheep and cattle sera with the structural antigens of alcelaphine herpesvirus-1 (malignant catarrhal fever virus).

Malignant catarrhal fever (MCF) is a disease of cattle and some other ruminants caused by alcelaphine herpesvirus-1 (AHV-1), a virus of wildebeest. The disease also occurs in the absence of wildebeest and is then thought to be caused by a viral agent harboured by the sheep. The structural proteins of AHV-1 have been used as antigens for the immunoblotting analysis of sera from wildebeest, sheep and cattle infected by either AHV-1 or the "sheep-associated" form of the disease. Wildebeest sera showed a uniform response reacting strongly with six polypeptides. Sheep sera also gave positive results but individual sera reacted with varying subsets of the antigens recognized by wildebeest. These results support the earlier suggestion that sheep harbour a herpesvirus related to AHV-1. A bovine serum from a case of MCF caused by AHV-1 also reacted only with a subset of the six wildebeest-reactive polypeptides. Sera from cattle affected with the "sheep-associated" form of the disease gave reactions in only two of the eight cases tested; both positive sera reacted to a few polypeptides only.

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Identification and characterization of the major proteins of malignant catarrhal fever virus.

Malignant catarrhal fever virus (MCFV), a gamma-herpesvirus, causes a severe inflammatory and lymphoproliferative disease of cattle and other susceptible ruminants. Polyclonal antisera and monoclonal antibodies (MAbs) to the Minnesota isolate of MCFV were produced and used to examine the characteristics of the viral proteins. Immunoprecipitation of antigens of the Minnesota isolate of MCFV with polyclonal antisera revealed at least 11 proteins with molecular masses ranging from 17 kDa to 145 kDa. Among 279 candidate anti-MCFV hybridomas, 14 were selected and clustered into six groups on the basis of the patterns of reactivity to viral proteins in immunoprecipitation and immunoblot. The group I MAbs exhibited strong neutralizing activity and recognized a glycosylation-dependent conformational epitope on a 110 kDa protein. The MAbs in group II bound a non-neutralizing conformational epitope on a 130 kDa non-glycosylated protein. A glycosylated protein complex of 115/110/105/78/45 kDa moieties was identified by the MAbs in group III. The MAbs in groups IV, V and VI reacted with non-glycosylated proteins of 36/34 kDa, 24 kDa and 17 kDa, respectively. Comparison of three MCFV isolates [the Minnesota isolate, the Austrian isolate (Au-732) and the African prototype isolate (WC-11)] revealed no apparent differences in immunoprecipitation patterns with the single exception that the 110 kDa protein of WC-11 was slightly smaller than its counterpart in the Minnesota isolate.

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Competitive inhibition enzyme-linked immunosorbent assay for antibody in sheep and other ruminants to a conserved epitope of malignant catarrhal fever virus.

Malignant catarrhal fever (MCF) is a severe, usually fatal, acute systemic disease syndrome of certain domestic and wild ruminants caused by members of the family Gammaherpesvirinae. Two distinct but closely related viruses cause clinically indistinguishable syndromes: one that is indigenous to the widebeest and the other that apparently is indigenous to domestic sheep. Neither the pathogenesis nor the epidemiology of sheep-associated MCF (SA-MCF) is understood, primarily because of a lack of adequate detection methods for the etiologic agent or antibody against it. No acceptably documented isolates of SA-MCF virus have been reported, and existing antibody assays suffer from significant cross-reactivity with other viruses. As a basis for a specific serologic assay, an attempt was made to identify an epitope conserved among all isolates of MCF viruses, by using a monoclonal antibody (MAb) produced against a previously reported U.S. isolate of MCF virus. A MAb (15-A) which bound a conserved epitope present on all four isolates of MCF virus examined was found. MAb 15-A did not react with eight common sheep and goat viruses or five common bovine viruses. Immunoprecipitation revealed that the 15-A epitope was located on the viral glycoprotein complex, with molecular masses of 115, 110, 105, 78, and 45 kDa. Sera from experimentally and naturally infected animals which yielded a similar glycoprotein complex immunoprecipitation pattern competed with MAb 15-A for its epitope. A competitive inhibition enzyme-linked immunosorbent assay (ELISA) based on MAb 15-A was therefore developed. The assay detected antibody in inapparently infected sheep and in cattle, deer, and bison with clinical MCF. Of the 149 serum samples from sheep associated with MCF outbreaks, 88 (55%) were seropositive by competitive inhibition ELISA.

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Malignant catarrhal fever in bison.

Malignant catarrhal fever was diagnosed in 3 herds of American bison (Bison bison) in South Dakota from 1973 to 1976. Clinical signs included depression, nasal and ocular discharge, conjunctivitis and keratitis, and diarrhea. Herd morbidity ranged from 3 to 53.8%, and mortality was 100%. At necropsy, ulcerative lesions were found throughout the alimentary tract, trachea, and bronchi. Microscopically, necrotizing vasculitis without thrombosis was found in virtually every organ examined.

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