Turkey herpesvirus: lack of oncogenicity for turkeys.
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Biomedical subjects
R L Witter
Publications and source records attributed to R L Witter.
Reticuloendotheliosis in breeder turkeys.
Reticuloendotheliosis virus (REV) was isolated at 21 weeks from a flock of breeder turkeys with lymphoid neoplasms. Except for about 2% mortality due to tumors mainly between 20 and 30 weeks of age, the livability and egg production of the flock were normal. Egg transmission as a source of infection seemed unlikely, because no REV antibodies or production problems were observed in two sister flocks (hatchmates) and in three progeny flocks, and because eggs obtained from the breeder flock at 45 weeks lacked REV group-specific antigen and produced poults negative for REV infection. The virus isolate, designated REV strain 339, produced an acute neoplastic disease when inoculated into young chickens.
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An enzyme-linked immunosorbent assay for the detection of antibodies to Marek's disease virus.
A reproducible enzyme-linked immunosorbent assay (ELISA) using Marek's disease virus (MDV)-infected cells for the detection of antibodies to MDV is described. The optimum number of MDV-infected chicken embryo fibroblasts (CEF) was 5 X 10(4)/well, and test sera were positive at 1:400 dilutions. Compared with a purified virus preparation, MDV-infected CEF produced high specific and low nonspecific reactivities. Wells coated with whole cells could be stored at 4 C or -20 C for at least 3 months without loss of reactivity. With antibody-negative sera, the cutoff absorbency was 0.20 units. The ELISA was 20-to-40-fold more sensitive than indirect immunofluorescence. Homologous combinations of antisera in wells coated with CEF infected with different MDV serotypes were more reactive at higher dilutions than were heterologous combinations. The procedure described is specific and suitable for large-scale screening of both chicken and monoclonal antibodies against MDV.
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Serologic evidence in commercial chicken and turkey flocks of infection with reticuloendotheliosis virus.
A serologic survey has documented probable infection with reticuloendotheliosis (RE) virus in 21.0% of 101 layer flocks, 23.5% of 85 broiler and broiler-breeder flocks, 2.3% of 43 backyard chicken flocks, and 4.8% of 125 turkey production and breeder flocks. However, no infection was detected in 72 grandparent lines of chicken breeding stocks representing meat-type and layer strains. The existence of natural infection was further supported by isolation of RE virus from one experimental chicken flock and two commercial turkey flocks. This study supports earlier but subsequently discounted data by Aulisio and Shelokov that exposure to RE virus occurs commonly among commercial chickens in the United States, as has also been reported in other countries.
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Development and characterization of a Marek's disease transplantable tumor in inbred line 72 chickens homozygous at the major (B) histocompatibility locus.
A serially transplantable Marek's disease (MD) tumor, designated MDCT-RP-3, was developed from an MD-virus-induced lymphoma (GA strain) in a pedigreed female chicken of the inbred B-histocompatible (B2/B2), line 72, and is the first MD tumor transplant to be developed in chickens both syngeneic and selected for susceptibility to MD. The MDCT-RP-3 tumor maintained its female karyotype through at least 80 passages in male 72 chickens. High doses of tumor cells caused progressively growing tumors at 5 days postinoculation and death of young 72 chicks in 7-10 days, whereas allogeneic chicks of other lines were less susceptible. Tumors frequently regressed when doses of tumor cells were low or older chickens were used. MD virus was rescued from MDCT-RP-3 cells in cell culture, and chickens surviving the early transplant response sometimes developed MD lymphomas. The tumor cells expressed MD-tumor-associated surface antigen (MATSA) and T-cell surface antigens. A serum raised in rabbits against MDCT-RP-3 cells and absorbed with normal 72 cells appeared to be reactive against MATSA on all MD tumor cells tested and is probably monospecific. Sera raised against MDCT-RP-3 in chickens also contained MATSA antibodies reactive against heterologous but not homologous MD tumor cells. Protection against transplantation of MDCT-RP-3 cells was not afforded by immunization with turkey herpesvirus vaccine. Some unvaccinated chickens that regressed MDCT-RP-3 transplant appeared to be partially immune to later development of MD lymphomas.
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Tolerance, viral shedding, and neoplasia in chickens infected with non-defective reticuloendotheliosis viruses.
Chickens inoculated as embryos with non-defective reticuloendotheliosis viruses (ndREVs) generally developed a "tolerant" infection characterized by lack of immunofluorescent antibody and by a viremia that persisted through 93 weeks. Chickens inoculated at hatching generally developed a "non-tolerant" infection characterized by antibody development that gradually waned as the chickens aged and by a transient or intermittent viremia. Although chickens tolerantly infected with ndREV strain T were immunodepressed, tolerance to ndREVs did not depend on immunodepression, because 17-to-20-week-old chickens tolerantly infected with ndREV strain CS were normal in antibody response to sheep red blood cells and Brucella abortus and in mitogen-stimulated blastogenesis of blood lymphocytes. Tolerantly infected dams shed low levels of gs antigen and virus into eggs at high frequencies; however, in two trials, congenital transmission of virus by strain-CS-infected dams was documented in only 2 of 42 and 1 of 132 progeny chicks. Eggs and progeny chicks from non-tolerantly infected dams were always negative for virus and gs antigen. After long latent period (17 to 93 weeks), ndREV-infected chickens developed lymphomas involving the bursa of Fabricius and other visceral organs at high frequency and developed sarcomas, carcinomas, and inflammatory nerve lesions at a lower frequency. The ability of ndREVs to induce tolerant and non-tolerant infection, virus- and antigen-shedding into eggs, and chronic neoplastic disease resembled that of lymphoid leukosis virus, another common avian retrovirus. Certain differences in epidemiological properties of these 2 viruses are discussed.
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Induction of lymphomas and tumor antigen by Marek's disease virus in turkeys.
Pathogenic Marek's disease (MD) virus (MDV) induced a high incidence of mortality and gross and microscopic lesions in turkey poults. Inoculated turkey poults became persistently viremic with MDV, although the levels of detectable circulating MDV were generally lower in turkeys than in similarly inoculated chickens. The early lytic phase of MD characterized by lymphoid cell destruction and the appearance of viral antigen in lymphoid organ was not as prominent in turkeys as in chickens. Gross MD lesions in turkeys were most prevalent in liver and spleen; peripheral nerves were involved infrequently. MD tumors in turkeys contained cells that reacted with antiserum prepared against chicken MD-tumor-associated surface antigen (MATSA); this result indicated that MDV induced cellular transformation in turkeys and the tumor-associated antigen in chicken and turkeys cross-reacted. Several in vitro-propagating B-cell lines were developed from the turkey lymphomas. As in chickens, MD in turkeys also resulted in immunodepression. Circulating lymphocytes from turkeys that eventually died of MD or had gross tumors at the end of the experiment were deficient in mitogenic response to Concanavalin A.
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Characteristics of Marek's disease viruses isolated from vaccinated commercial chicken flocks: association of viral pathotype with lymphoma frequency.
Fifty-three Marek's disease (MD) virus (MDV) isolates were obtained from turkey-herpesvirus-vaccinated broiler or layer flocks with excessive MD losses, from control field flocks without excessive MD losses, and from laboratory collections. Twelve isolates were typed as very virulent (vvMDVs) on the basis of excessive pathogenicity for vaccinated chickens, 31 were typed as virulent (vMDVs), and 10 were typed as nonpathogenic (npMDVs). The npMDVs could be distinguished from turkey herpesviruses by cultural and serologic criteria. Compared with standard vMDVs, the vvMDVs appeared clearly more pathogenic; they caused greater depression in body and bursal weights and induced more deaths through the early mortality syndrome, more lymphomas, and more visceral and fewer neural lymphomas in susceptible and resistant chickens. However, no antigenic differences between vvMDVs and vMDVs were detected. The vvMDVs were obtained from both broiler and layer flocks in five widely separated states but may only recently have become prevalent, since none were represented among 10 MDV isolates obtained before 1975. The frequency of isolation of vvMDVs from flocks with excessive MD losses (9/27) was threefold higher than that from control flocks (1/10), suggesting an association of this viral pathotype with vaccine breaks. The npMDVs were also widely distributed but were isolated only from control flocks, thus suggesting that npMDVs may augment turkey-herpesvirus-induced vaccinal immunity.
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Detection of antibodies against reticuloendotheliosis viruses by an enzyme-linked immunosorbent assay.
A microplate indirect enzyme-linked immunosorbent assay (ELISA) for antibodies against reticuloendotheliosis virus (REV) was consistently more sensitive than indirect immunofluorescent-antibody tests. Limits of antibody detection were comparable to those obtained in virus neutralizations. Detection of REV-infected chickens long after infection and after immunofluorescent antibody has waned makes ELISA especially suitable for screening chicken flocks.
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Studies of reticuloendotheliosis virus-induced lymphomagenesis in chickens.
Seventy-three percent of chickens inoculated with the chick syncytial strain of reticuloendotheliosis virus (REV) at hatching developed lymphomas by 39 weeks of age. Neonatal treatment with cyclophosphamide or surgical bursectomy at 2, 4, 8, or 12 weeks of age significantly (P less than 0.01) reduced lymphoma development. In a further experiment, surgical bursectomy of REV-infected chickens followed by intravenous inoculation of the chickens with a single cell suspension of their own bursa cells at 2, 4, 9, or 13 weeks of age resulted in lymphoid tumors in chickens treated at 9 or 13 weeks but not in chickens treated at 2 or 4 weeks of age. Furthermore, this treatment did not shorten the incubation period for lymphoma development. These findings argue very strongly that transforming target cells are primarily in the bursa of Fabricius. The data also suggest that a minimum residency of 4 weeks in the bursa is required for infected bursa cells to become transformed. Therefore, lymphomagenesis induced by REV in chickens appears similar to that induced by the avian leukosis virus group.
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Embryo vaccination against Marek's disease with serotypes 1, 2 and 3 vaccines administered singly or in combination.
Marek's disease virus (MDV) vaccines of serotypes 1 and 2 administered in 18-day-old embryonated eggs induced better protection against post-hatch challenge at 3 days with virulent MDV than vaccines given at hatch. Embryonal vaccination with a polyvalent vaccine containing equal quantities of serotypes 1 and 2 of MDV and serotype 3 virus (turkey herpesvirus, HVT) was also significantly more effective than post-hatch vaccination. These and earlier results indicate that protective efficacy of single or combined Marek's disease vaccine serotypes against post-hatch challenge at 3 days can be substantially improved if the vaccines are injected into 18-day embryos rather than at hatch. Injection of vaccines of serotypes 1 or 2 into embryonated eggs or hatched chicks did not cause detectable gross or microscopic lesions in chickens. Vaccine viruses of serotypes 1 and 2 could be isolated from spleen cells of chickens 1 week post-vaccination, and the titer of recoverable viruses was higher in chickens that received the vaccines at the 18th day of embryonation than in chickens vaccinated at hatch. Although embryo vaccination with HVT usually provided better protection than post-hatch vaccination against early post-hatch challenge with variant pathotypes of MDV, the protection was poor regardless of vaccination protocol. If challenge with variant pathotypes of MDV was delayed until embryonally or post-hatch HVT-vaccinated chickens were 21 days of age, protection of chickens by HVT was not enhanced. Thus, resistance induced by embryonal vaccination with HVT was qualitatively similar to that induced by post-hatch vaccination with this virus.
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Immunization against Marek's disease transplantable cell lines.
Continuous passage of MDCC-RP1, a highly tumorigenic Marek's disease (MD) lymphoblastoid cell line, in cell culture resulted in a gradual loss in ability of the cell line to cause progressive tumors in susceptible day-old chicks. Inoculation of day-old chicks with high-cell-culture-passaged (187th to 417th) nontumorigenic MDCC-RP1 cells gave excellent protection against challenge at 8 days with low-passaged tumorigenic MDCC-RP1 cells but failed to protect against primary tumors caused by inoculation with MD virus. Vaccination with the herpesvirus of turkeys, on the other hand, protected the chickens well against primary tumors caused by MD virus and against transplantable tumors caused by tumorigenic MDCC-RP1 cells, but it did not protect as well against another MD lymphoblastoid cell line, MDCC-RP4. It is unlikely, therefore, that vaccines prepared from passaged MDCC-RP1 cell lines will have value for protecting chickens against MD in the field.
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Field trials to test the efficacy of polyvalent Marek's disease vaccines in broilers.
The efficacies of trivalent (Md11/75C + SB-1 + HVT), bivalent (SB-1 + HVT), and turkey herpesvirus (HVT) vaccines against Marek's disease (MD) were compared in commercial broiler flocks in four trials involving 11 farm locations and 486,300 chickens. In all four trials, chickens receiving polyvalent vaccines had lower leukosis (MD) condemnation rates than chickens vaccinated with HVT alone; when data were summarized for each vaccine type in each trial, condemnation rates for the bivalent- or trivalent-vaccinated groups were 56-96% (mean 78%) lower than those for HVT-vaccinated chickens. Polyvalent vaccination was clearly mor efficacious than HVT in 8 of 11 individual farms, although it did not always reduce leukosis condemnations to acceptable levels. Body weights of chickens vaccinated with polyvalent vaccines did not differ consistently from those vaccinated with HVT. Chickens inoculated with the trivalent vaccine had slightly lower overall leukosis condemnation rates (0.24%) than those inoculated with the bivalent vaccine (0.45%) in trials 1-3, where direct comparisons were made. Bivalent vaccines containing either 1,500 or 200 plaque-forming units of SB-1 virus were equally effective; thus, HVT may need to be supplemented with only small amounts of SB-1 to obtain the benefits of protective synergism. SB-1 virus did not appear to carry over from polyvalent-vaccinated flocks to subsequent HVT-vaccinated flocks in the same houses, even when old litter was used.
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Hatchery-related contact transmission and short- term small-group-rearing as related to lymphoid-leukosis-virus-eradication programs.
Pathogen-free chickens highly susceptible to lymphoid leukosis virus (LLV) were used to study the role of hatchery-related contact transmission of LLV. In one experiment, the efficiency of short-term small-group-rearing in conventional-type rearing units to prevent contact transmission of LLV from infected to uninfected groups was evaluated. Results obtained from these experiments suggest that LLV is not transmitted by congenitally infected chicks to uninfected hatchmates in the hatcher. However, LLV can be transmitted by congenitally infected chicks to uninfected hatchmates during standard manual vent sexing. Rate of contact transmission was lower in chickens reared on wire-mesh floors than in chickens reared on solid floors. Short-term procedures in which chicks were reared in colony cages and brooder batteries effectively reduced the transmission of LLV by infected groups of hatching chicks to uninfected groups. All these procedures should facilitate the rearing of small groups of chicks with little risk of infection for a period sufficient to conduct virus assays, an essential step in LLV eradication.
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Characteristics of CVI988/Rispens and R2/23, two prototype vaccine strains of serotype 1 Marek's disease virus.
Studies were focused on two attenuated serotype 1 Marek's disease (MD) vaccine viruses, CVI988/Rispens (passage 42) and R2/23 (passage 105). Both serotype 1 vaccine viruses provided much higher levels of protection than the prototype MD vaccine, turkey herpesvirus (HVT); the best protection was generally provided by CVI988/Rispens when compared with other vaccines. The efficacy of neither serotype 1 vaccine was improved by mixture with viruses of other serotypes (synergism). No differences between the two serotype 1 vaccines were revealed by cross-neutralization tests, thus excluding preferential in vivo neutralization by maternal antibodies as an explanation for differences in protective efficacy. Neither vaccine strain induced MD lesions or reduced growth rates in 8- or 18-week trials. Neither virus depressed humoral or cellular immune responses to antigenic challenge at 3 or 15 days after vaccination. Both virus strains exhibited altered characteristics during serial backpassage; R2/23 acquired increased oncogenic potential, and CVI988/Rispens acquired the potential for increased viremia titers, accompanied by an increased frequency of both histologic nerve lesions and gross thymic atrophy. During backpassage trials, contact spread was not observed for R2/23 and, surprisingly, seemed relatively limited for CVI988/Rispens. Studies on these two serotype 1 strains generally support the safety and efficacy of the serotype 1 class of MD vaccines.
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Partial inhibition by turkey herpesvirus of serotype 2 Marek's disease virus plaque formation and in vivo infectivity.
The increased use of serotype 2 Marek's disease virus (MDV) and serotype 3 turkey herpesvirus (HVT) as components of effective bivalent vaccines against Marek's disease (MD) prompted studies on the possible interactions of these two viruses in vitro and in vivo. The replication of the SB-1 strain of MDV was compared with replication of the FC126/2 strain of HVT in chickens and cell cultures infected with one or both viruses. Replication of MDV was reduced in the presence of HVT in both in vitro and in vivo systems. MDV plaque counts in dually infected chicken embryo fibroblast cultures inoculated with tissue-culture-propagated viruses were reduced by up to 91%; however, no inhibition was noted when inocula consisted of virus-infected buffy-coat cells. Plaque formation by MDV in chicken embryo fibroblast cultures was inhibited by virus-free conditioned medium from HVT-infected cultures. This conditioned medium also inhibited growth of vesicular stomatitis virus in a standard interferon assay. In chickens inoculated with both MDV and HVT, MDV viremia titers were lower and the dose required to infect 50% of susceptible chickens was increased 13-fold compared with chickens inoculated with MDV alone. In spite of these findings, there was no evidence that high concentrations of HVT interfered with either the ability of MDV to induce protective synergism in vivo or the protective efficacy of bivalent vaccines. No reciprocal inhibitory effects of MDV on the replication of HVT in vivo or in vitro were noted.
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Identification and localization of glycoprotein B expression in lymphoid tissues of chickens infected with turkey herpesvirus.
One-day-old chickens were inoculated with turkey herpesvirus (HVT). Using an indirect immunofluorescence assay with a monoclonal antibody against HVT glycoprotein B (gB), we determined the course of productive HVT infection in peripheral blood mononuclear cells (PBMCs), spleen, thymus, and bursa. PBMCs were examined from days 4 through 35 postinfection (PI). The spleen, thymus, and bursa were examined from 21 through 70 days PI. Although productive infection in PBMCs was detected at 4 to 12 days PI, it ended by 14 days PI. Splenic cells expressed gB at 21, 28, 35, and 70 days PI, whereas the thymus was positive for gB expression at 21 and 35 days PI. The bursa was never positive for gB expression. At 21, 28, 35, and 70 days PI, plaque formation after co-cultivation of PBMCs with chicken embryo fibroblasts indicated the presence of HVT in infected chickens by co-cultivation assays. On the basis of indirect immunofluorescence assay, gB expression in the spleen and thymus indicates a productive HVT infection in chickens.
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Serotype specificity of B-haplotype influence on the relative efficacy of Marek's disease vaccines.
B-haplotype genes in the chicken were previously shown to differentially influence vaccine efficacy against challenge with very virulent Marek's disease virus according to the type of Marek's disease (MD) vaccine used. To determine whether MD vaccines of the same serotype gave comparable levels of protection against MD in chickens of the same haplotype challenged with MD virus strain Md5, two serotype 1 and two serotype 2 vaccines were compared with one serotype 3 vaccine using chickens of 15-B-congenic lines. There was a strong correlation in development of MD lesions among chickens of the different lines receiving the two serotype 2 vaccines (r = 0.94) as well as among chickens receiving the two serotype 1 vaccines (r = 0.76). The serotype 1 vaccines were preferable for B2, B13, B15, and B21, but serotype 2 vaccines were more protective for B5 chickens. The two serotype 2 vaccines gave equivalent protection; however, of the serotype 1 vaccines, CVI988/Rispens provided more protection than Md11/75c/R2/23. We conclude that the B-haplotype influence on MD vaccine efficacy is dependent on the serotype of the vaccine.
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