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1.
J Vet Sci ; 25(5): e61, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39231786

RESUMEN

IMPORTANCE: Ovine pulmonary adenomatosis (OPA) and maedi-visna disease (MVD) are chronic and progressive infectious diseases in sheep caused by Jaagsiekte sheep retrovirus (JSRV) and maedi-visna virus (MVV), respectively. OBJECTIVE: To investigate the pathological changes and conduct viral gene analysis of OPA and MVD co-occurrence in Inner Mongolia, China. METHODS: Using gross pathology, histopathology, immunohistochemistry, ultrastructural pathology, PCR, and sequence analysis, we investigated the concurrent infection of JSRV and MVV in 319 Dorper rams slaughtered in a private slaughterhouse in Inner Mongolia, in 2022. RESULTS: Of the 319 rams included, 3 showed concurrent JSRV and MVV infection. Gross lung pathology showed diffuse enlargement, consolidation, and greyish-white miliary nodules on the lung surface; the trachea was filled with a white foamy fluid; hilar and mediastinal lymph nodes were significantly enlarged. Histopathology results revealed typical OPA and MVD lesions in the lung tissue. Immunohistochemical results were positive for JSRV envelope protein (Env) in the tumor cells and MVV CA in alveolar macrophages. Transmission electron microscopy showed several virions and autophagosomes in the lung tissue, severely damaged mitochondria, and the induced mitophagy. Nucleotide sequences obtained for JSRV env and MVV gag showed the highest homology with the Inner Mongolian strains of JSRV env (JQ837489) and MVV gag (MW248464). CONCLUSIONS AND RELEVANCE: Our study confirmed that OPA and MVD co-occurrence and identified the pathological changes in Inner Mongolia, China, thereby providing references for the identification of concurrent JSRV and MVV infections.


Asunto(s)
Retrovirus Ovino Jaagsiekte , Adenomatosis Pulmonar Ovina , Virus Visna-Maedi , Animales , Ovinos , China , Adenomatosis Pulmonar Ovina/virología , Adenomatosis Pulmonar Ovina/patología , Masculino , Coinfección/veterinaria , Coinfección/virología , Filogenia , Pulmón/virología , Pulmón/patología , Enfermedades de las Ovejas/virología , Enfermedades de las Ovejas/patología , Visna/virología , Visna/patología
2.
Genes (Basel) ; 15(8)2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39202379

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is an infectious, neoplastic lung disease of sheep that causes significant animal welfare and economic issues throughout the world. Understanding OPA pathogenesis is key to developing tools to control its impact. Central to this need is the availability of model systems that can monitor and track events after Jaagsiekte sheep retrovirus (JSRV) infection. Here, we report the development of an experimentally induced OPA model intended for this purpose. Using three different viral dose groups (low, intermediate and high), localised OPA tumour development was induced by bronchoscopic JSRV instillation into the segmental bronchus of the right cardiac lung lobe. Pre-clinical OPA diagnosis and tumour progression were monitored by monthly computed tomography (CT) imaging and trans-thoracic ultrasound scanning. Post mortem examination and immunohistochemistry confirmed OPA development in 89% of the JSRV-instilled animals. All three viral doses produced a range of OPA lesion types, including microscopic disease and gross tumours; however, larger lesions were more frequently identified in the low and intermediate viral groups. Overall, 31% of JSRV-infected sheep developed localised advanced lesions. Of the sheep that developed localised advanced lesions, tumour volume doubling times (calculated using thoracic CT 3D reconstructions) were 14.8 ± 2.1 days. The ability of ultrasound to track tumour development was compared against CT; the results indicated a strong significant association between paired CT and ultrasound measurements at each time point (R2 = 0.799, p < 0.0001). We believe that the range of OPA lesion types induced by this model replicates aspects of naturally occurring disease and will improve OPA research by providing novel insights into JSRV infectivity and OPA disease progression.


Asunto(s)
Adenocarcinoma del Pulmón , Modelos Animales de Enfermedad , Retrovirus Ovino Jaagsiekte , Neoplasias Pulmonares , Adenomatosis Pulmonar Ovina , Animales , Retrovirus Ovino Jaagsiekte/patogenicidad , Ovinos , Adenomatosis Pulmonar Ovina/virología , Adenomatosis Pulmonar Ovina/patología , Adenocarcinoma del Pulmón/virología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Infecciones por Retroviridae/virología , Infecciones por Retroviridae/patología , Infecciones por Retroviridae/veterinaria , Tomografía Computarizada por Rayos X
4.
Open Vet J ; 12(2): 264-272, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35603075

RESUMEN

Background: Ovine pulmonary adenocarcinoma (OPA), caused by Jaagsiekte sheep retrovirus (JSRV), is a contagious neoplastic disease in sheep characterized by chronic respiratory signs, inducing the transformation of secretory epithelial cells of the distal respiratory tract. Aims: To perform clinical, epidemiological, and molecular studies with evaluation of some predisposing factors at the herd level of OPA infection in sheep in Al-Qadisiyah Province, Iraq. Methods: The first step of the study was undertaken to evaluate the clinical cases of OPA in naturally infected sheep and correlation with observing respiratory signs. Seventy-five sheep with chronic respiratory signs were examined clinically, and by molecular and sequences analysis. The second step was the epidemiological part that was carried out on 195 randomly selected animals from 30 flocks, with the prevalence rate based on PCR; sex, age, and size of flocks were assessed, as well as macroscopic and microscopic features of the neoplastic lung. Deep nasal swabs and nasal secretion were collected from all animals. RNA extraction and RT-PCR were also carried out. Results: The results showed that 12 (16%) samples were positive for OPA, based on env gene-specific primers. Nucleotide sequences of partial 545 bp of the env gene showed (0.07-0.12) variations from global strains presented in the NCBI database. The prevalence rate of OPA was 21/195 (10.76%) with PCR. The epidemiological factors analysis showed that there was no effect of sex and herd size on the prevalence rates (p ≥ 0.01), whereas age was significantly affected and the age of 2-4 years was more susceptible (p ≥ 0.01). Gross and microscopic examinations were discussed with the confirmation of an OPA infection. Conclusion: The current study provides useful data about the clinical and epidemiological features of JSRV that is circulating in sheep of Iraq, and concludes that epidemiological studies and disease control may require multi-diagnostic assays.


Asunto(s)
Retrovirus Ovino Jaagsiekte , Adenomatosis Pulmonar Ovina , Enfermedades de las Ovejas , Animales , Irak/epidemiología , Retrovirus Ovino Jaagsiekte/genética , Reacción en Cadena de la Polimerasa/veterinaria , Adenomatosis Pulmonar Ovina/epidemiología , Adenomatosis Pulmonar Ovina/patología , Ovinos/genética , Enfermedades de las Ovejas/epidemiología
5.
Arch Virol ; 166(3): 831-840, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33486631

RESUMEN

Ovine pulmonary adenomatosis (OPA) is caused by jaagsiekte sheep retrovirus (JSRV) and is a chronic, progressive, and infectious neoplastic lung disease in sheep, which causes significant economic losses to the sheep industry. Neither a vaccine nor serological diagnostic methods to detect OPA are available. We performed a JSRV infection survey in sheep using blood samples (n = 1,372) collected in the three northeastern provinces of China (i.e., Inner Mongolia, Heilongjiang, and Jilin) to determine JSRV infection status in sheep herds using a real-time PCR assay targeting the gag gene of JSRV. The ovine endogenous retrovirus sequence was successfully amplified in all sheep samples tested (296 from the Inner Mongolia Autonomous Region, 255 from Jilin province, and 821 from Heilongjiang province). Subsequently, we attempted to distinguish exogenous JSRV (exJSRV) and endogenous JSRV (enJSRV) infections in these JSRV-positive samples using a combination assay that identifies a ScaI restriction site in an amplified 229-bp fragment of the gag gene of JSRV and a "LHMKYXXM" motif in the cytoplasmic tail region of the JSRV envelope protein. The ScaI restriction site is present in all known oncogenic JSRVs but absent in ovine endogenous retroviruses, while the "LHMKYXXM" motif is in all known exJSRVs but not in enJSRVs. Interestingly, one JSRV strain (HH13) from Heilongjiang province contained the "LHMKYXXM" motif but not the ScaI enzyme site. Phylogenetic analysis showed that strain HH13 was closely related to strain enJSRV-21 reported in the USA, indicating that HH13 could be an exogenous virus. Our results provide valuable information for further research on the genetic evolution and pathogenesis of JSRV.


Asunto(s)
Retrovirus Endógenos/genética , Productos del Gen env/genética , Retrovirus Ovino Jaagsiekte/genética , Adenomatosis Pulmonar Ovina/epidemiología , Adenomatosis Pulmonar Ovina/patología , Secuencias de Aminoácidos/genética , Animales , Secuencia de Bases , China/epidemiología , ADN Viral/análisis , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Evolución Molecular , Genoma Viral/genética , Retrovirus Ovino Jaagsiekte/clasificación , Filogenia , Reacción en Cadena en Tiempo Real de la Polimerasa , Mapeo Restrictivo , Homología de Secuencia de Ácido Nucleico , Ovinos
6.
J Virol Methods ; 284: 113923, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32615131

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is a globally occurring tumor of lung epithelium which seriously affects the development of sheep farming. In our research, lung tissues of 3 naturally infected OPA individuals and 3 healthy individuals (2-4 years old) were collected. RNA was extracted for transcriptome analysis and reference gene selection. According to transcriptome analysis, 7 candidate reference genes (eukaryotic translation initiation factor 1, EIF1; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; beta-actin, ACTB; GABA Type A receptor-associated protein, GABARAP; activating transcription factor 4, ATF4; ribosomal protein S15, RPS15; and Y-Box binding protein 1, YBX1) showed fragments per kilobase of transcript per million fragments mapped (FPKM) values > 200.0 and standard errors of the means (SEM) < 20.0. Expression of the above candidate reference genes was evaluated by Real-time quantitative polymerase chain reaction (RT-qPCR) combined with the analysis using GeNorm, NormFinder, and BestKeeper software. Comprehensive analysis of the results showed that ACTB was the most stable one, followed by EIF1 and GABARAP. Then, expression stability of the above three genes were validated, suggesting as suitable reference genes in sheep lung tissue, in additional 30 OPA-affected lung tissues and 10 healthy ovine lung tissues. Finally, our findings will be helpful for the subsequent study on the tumorigenic mechanism of OPA.


Asunto(s)
Perfilación de la Expresión Génica/normas , Pulmón/metabolismo , Adenomatosis Pulmonar Ovina/metabolismo , Actinas/genética , Animales , Factor 1 Eucariótico de Iniciación/genética , Femenino , Perfilación de la Expresión Génica/métodos , Retrovirus Ovino Jaagsiekte , Pulmón/patología , Proteínas Asociadas a Microtúbulos/genética , Adenomatosis Pulmonar Ovina/genética , Adenomatosis Pulmonar Ovina/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estándares de Referencia , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Ovinos
7.
J Vet Diagn Invest ; 32(1): 152-155, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31884891

RESUMEN

Betaretrovirus-induced transmissible respiratory tumors in sheep arise at 2 distinct anatomic locations, either deep in the lung tissue caused by jaagsiekte sheep retrovirus (JSRV) or in the nasal cavity induced by ovine enzootic nasal tumor virus (ENTV-1). JSRV and ENTV-1 are found in many countries worldwide and have a significant economic and animal health impact. Although JSRV is endemic in sheep in the British Isles, ENTV-1 has not been reported. We report herein a nasal adenocarcinoma in a cull 8-y-old Belclare ewe from Ireland. The gross and microscopic features and immunohistochemistry results were consistent with an ENTV-1-associated tumor. However, differential PCR, using primers specific to regions of divergent sequence between the viruses, was performed on different parts of the adenocarcinoma and produced consistent results: positive for JSRV and negative for ENTV-1. An association of JSRV with nasal adenocarcinoma in sheep has not been reported previously, to our knowledge. Our case shows the necessity of using PCR in combination with immunohistochemistry to reach an accurate etiologic diagnosis, which is of importance in countries currently free of ENTV-1.


Asunto(s)
Adenocarcinoma/veterinaria , Retrovirus Ovino Jaagsiekte , Neoplasias Nasales/veterinaria , Adenomatosis Pulmonar Ovina/virología , Adenocarcinoma/epidemiología , Adenocarcinoma/virología , Animales , Femenino , Irlanda/epidemiología , Neoplasias Nasales/epidemiología , Neoplasias Nasales/virología , Adenomatosis Pulmonar Ovina/epidemiología , Adenomatosis Pulmonar Ovina/patología , Ovinos
8.
J Virol ; 93(21)2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31434729

RESUMEN

Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a neoplastic lung disease of sheep. OPA is an important economic and welfare issue for sheep farmers and a valuable naturally occurring animal model for human lung adenocarcinoma. Here, we used RNA sequencing to study the transcriptional response of ovine lung tissue to infection by JSRV. We identified 1,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, including many genes with roles in carcinogenesis and immunomodulation. The differential expression of selected genes was confirmed using immunohistochemistry and reverse transcription-quantitative PCR. A key finding was the activation of anterior gradient 2, yes-associated protein 1, and amphiregulin in OPA tumor cells, indicating a role for this oncogenic pathway in OPA. In addition, there was differential expression of genes related to innate immunity, including genes encoding cytokines, chemokines, and complement system proteins. In contrast, there was little evidence for the upregulation of genes involved in T-cell immunity. Many genes related to macrophage function were also differentially expressed, reflecting the increased abundance of these cells in OPA-affected lung tissue. Comparison of the genes differentially regulated in OPA with the transcriptional changes occurring in human lung cancer revealed important similarities and differences between OPA and human lung adenocarcinoma. This study provides valuable new information on the pathogenesis of OPA and strengthens the use of this naturally occurring animal model for human lung adenocarcinoma.IMPORTANCE Ovine pulmonary adenocarcinoma is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV). OPA is a significant economic problem for sheep farmers in many countries and is a valuable animal model for some forms of human lung cancer. Here, we examined the changes in host gene expression that occur in the lung in response to JSRV infection. We identified a large number of genes with altered expression in infected lung, including factors with roles in cancer and immune system function. We also compared the data from OPA to previously published data from human lung adenocarcinoma and found a large degree of overlap in the genes that were dysregulated. The results of this study provide exciting new avenues for future studies of OPA and may have comparative relevance for understanding human lung cancer.


Asunto(s)
Retrovirus Ovino Jaagsiekte/fisiología , Pulmón/virología , Adenomatosis Pulmonar Ovina/genética , Adenocarcinoma del Pulmón/genética , Animales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/genética , Adenomatosis Pulmonar Ovina/metabolismo , Adenomatosis Pulmonar Ovina/patología , Adenomatosis Pulmonar Ovina/virología , Ovinos
9.
J Vet Diagn Invest ; 28(3): 249-56, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27016721

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring cancer in sheep that is caused by the Jaagsiekte sheep retrovirus (JSRV). Because the pathologic and epidemiologic features of OPA are similar to those of bronchoalveolar carcinoma in humans, OPA is considered a useful animal model for pulmonary carcinogenesis. In this study, 3,512 lungs from various breeds of sheep were collected and macroscopically examined. OPA was identified in 30 sheep, and samples of these animals were further examined by histologic, immunohistochemical (p53 protein, surfactant protein A [SP-A], proliferating cell nuclear antigen [PCNA], JSRV matrix protein [MA]), and PCR methods. Papillary or acinar adenocarcinomas were detected microscopically in the affected areas. Immunoreactivity for p53 PAb240 was detected in 13 sheep, whereas p53 DO-1 was not detected in any of the OPA animals. PCNA immunoreactivity was recorded in 27 animals. SP-A and JSRV MA protein was immunopositive in all 30. JSRV proviral DNA was detected by PCR analysis in all of the lung samples collected from OPA animals. In addition, the pulmonary SP-A levels were increased in tumor cells. The results of this study suggest that PCNA and p53 protein expression may be useful indicators in monitoring malignancy of pulmonary tumors.


Asunto(s)
Adenomatosis Pulmonar Ovina/virología , Animales , Inmunohistoquímica/veterinaria , Retrovirus Ovino Jaagsiekte/patogenicidad , Pulmón/patología , Reacción en Cadena de la Polimerasa/veterinaria , Adenomatosis Pulmonar Ovina/metabolismo , Adenomatosis Pulmonar Ovina/patología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Ovinos , Proteína p53 Supresora de Tumor/metabolismo
10.
Bing Du Xue Bao ; 31(3): 217-25, 2015 May.
Artículo en Chino | MEDLINE | ID: mdl-26470525

RESUMEN

To carry out pathologic diagnoses and whole-genome sequence analyses of the Jaagsiekte sheep retrovirus (JSRV) in Xinjiang, China, we first observed sheep suspected to have the JSRV. Then, the extracted virus suspension was observed by transmission electron microscopy (TEM). Total RNAs from lungs of JSRV-infected sheep were extracted and reverse-transcribed using a cDNA synthesis kit. Six pairs of primers were designed according to the exogenous reference virus strain (AF105220). Reverse transcription-polymerase chain reaction was carried out from JSRV-infected tissue, and the whole genome of the JSRV sequenced. Our results showed: flow of nasal fluid ("wheelbarrow test"); different sizes of adenoma lesions in the lungs; papillary hyperplasia of alveolar epithelial cells; alveolar cavity filled with macrophages; dissolute nuclei in central lesions. TEM revealed JSRV particles with a diameter of 88 nm to 125. 4 nm. The full-length of the viral genome sequence was 7456 bp. BLAST analyses showed nucleotide homology of 96% and 95% compared with that of the representative strain from the USA (AF105220) and UK (AF357971). Nucleotide homology was 89.8% and 89.9% compared with the endogenous Jaagsiekte sheep retrovirus, Inner Mongolia strain (DQ838493) and USA strain (EF680300). The specific pathogenic amino-acid sequence "YXXM" was found in the TM district, similar to the exogenous JSRV: this gene has been reported to be oncogenic. This is the first report of the complete genomic sequence of the exogenous JSRV from Xinjiang, and could lay the foundation for study of the biological characteristics and pathogenic mechanisms of the pulmonary adenomatosis virus in sheep.


Asunto(s)
Genoma Viral , Retrovirus Ovino Jaagsiekte/genética , Adenomatosis Pulmonar Ovina/virología , Secuencia de Aminoácidos , Animales , China , Retrovirus Ovino Jaagsiekte/clasificación , Retrovirus Ovino Jaagsiekte/aislamiento & purificación , Retrovirus Ovino Jaagsiekte/patogenicidad , Pulmón/patología , Pulmón/virología , Datos de Secuencia Molecular , Filogenia , Adenomatosis Pulmonar Ovina/patología , Ovinos , Proteínas Virales/química , Proteínas Virales/genética , Virulencia
11.
J S Afr Vet Assoc ; 85(1): 932, 2014 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-24831538

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is a contagious tumour in sheep caused by jaagsiekte sheep retrovirus (JSRV). This tumour originates from the pneumocyte type II and Clara cells and grossly appears as hard, prominent nodules in different lobes. The clinical signs of the disease are similar to those of other chronic respiratory diseases and are not pathogonomic. Therefore, post mortem examinations and histopathological studies are the most reliable ways to diagnose OPA, particularly subclinical cases of this neoplasm. In this study, out of 1000 sheep lungs grossly inspected, 50 animals were suspected of OPA. The suspected lungs as well as 25 apparently normal lungs were examined by histopathological and PCR methods. The proviral DNA was detected in 1/25 apparently normal lungs and 8/50 of the suspected lungs and subsequently confirmed by histopathological studies. The PCR-positive lung samples from five sheep revealed lesions of 'atypical' OPA and those from three sheep showed the 'classic' form of the disease. The tumours were multifocal and the masses were distributed throughout the cranioventral and diaphragmatic lung lobes. The stroma of the tumours in the atypical cases was more severely affected with inflammatory cell infiltration and connective tissue proliferation. The histopathological characteristics of maedi including hyperplasia of the perivascular and peribronchiolar lymphoid cells, interstitial lymphoplasmacytic infiltration and smooth muscle hyperplasia were also associated with OPA, especially the atypical form of this adenocarcinoma. Atypical OPA was more prevalent than the classic form. Geographic and climatic conditions, duration of exposure to the virus and the immune status of individual animals might be responsible for the differences between the two pathological entities of OPA.


Asunto(s)
Retrovirus Ovino Jaagsiekte , Reacción en Cadena de la Polimerasa/veterinaria , Adenomatosis Pulmonar Ovina/patología , Animales , Irán/epidemiología , Adenomatosis Pulmonar Ovina/epidemiología , Adenomatosis Pulmonar Ovina/virología , Ovinos
12.
J Comp Pathol ; 150(2-3): 138-47, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24176105

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by jaagsiekte sheep retrovirus (JSRV). This study examines immunohistochemically solitary lung nodules considered as early OPA lesions from 11 sheep infected naturally by JSRV. All 11 neoplastic nodules exhibited features of adenocarcinoma and in four of them mesenchymal growth was also observed. Both types of lesion were labelled with antibody specific for JSRV-Env. In two cases infiltrating lymphoreticular cells also contained JSRV-Env. All tumours had a high Ki67 labelling index and variably contained cells expressing CC10 (a marker of Clara cells (CCs)), SPC (a marker of type II pneumocytes), p63 and keratin 14 (markers for stem/progenitor cells of the lung airway epithelia). Tumours with mesenchymal growth had intense expression of vimentin and desmin, weak expression of smooth muscle actin and did not express pancytokeratin and p63. Both epithelial and mesenchymal proliferations did not express the stem cell markers CD90 and CD117, but some tumour infiltrating cells expressed CD133. Solitary OPA tumours can therefore be adenocarcinomas or mixed tumours and have a heterogeneous cellular composition, containing groups of cells expressing markers that characterize local progenitor cells involved in lung repair.


Asunto(s)
Retrovirus Ovino Jaagsiekte/aislamiento & purificación , Pulmón/patología , Adenomatosis Pulmonar Ovina/patología , Animales , Biomarcadores/metabolismo , Queratina-14/metabolismo , Pulmón/metabolismo , Adenomatosis Pulmonar Ovina/metabolismo , Ovinos , Células Madre/metabolismo , Células Madre/patología , Proteínas Supresoras de Tumor/metabolismo , Vimentina/metabolismo
13.
J Virol ; 87(19): 10752-62, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23903827

RESUMEN

Understanding the factors governing host species barriers to virus transmission has added significantly to our appreciation of virus pathogenesis. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer of sheep that has rarely been found in goats. In this study, in order to further clarify the pathogenesis of OPA, we investigated whether goats are resistant to JSRV replication and carcinogenesis. We found that JSRV induces lung tumors in goats with macroscopic and histopathological features that dramatically differ from those in sheep. However, the origins of the tumor cells in the two species are identical. Interestingly, in experimentally infected lambs and goat kids, we revealed major differences in the number of virus-infected cells at early stages of infection. These differences were not related to the number of available target cells for virus infection and cell transformation or the presence of a host-specific immune response toward JSRV. Indeed, we also found that goats possess transcriptionally active endogenous retroviruses (enJSRVs) that likely influence the host immune response toward the exogenous JSRV. Overall, these results suggest that goat cells, or at least those cells targeted for viral carcinogenesis, are not permissive to virus replication but can be transformed by JSRV.


Asunto(s)
Adenocarcinoma/etiología , Transformación Celular Neoplásica/patología , Interacciones Huésped-Patógeno , Retrovirus Ovino Jaagsiekte/patogenicidad , Neoplasias Pulmonares/etiología , Adenomatosis Pulmonar Ovina/virología , Replicación Viral , Adenocarcinoma/patología , Animales , Western Blotting , Células Cultivadas , Femenino , Técnica del Anticuerpo Fluorescente , Cabras , Técnicas para Inmunoenzimas , Hibridación in Situ , Retrovirus Ovino Jaagsiekte/fisiología , Neoplasias Pulmonares/patología , Adenomatosis Pulmonar Ovina/complicaciones , Adenomatosis Pulmonar Ovina/patología , ARN Mensajero/genética , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ovinos
14.
J Trace Elem Med Biol ; 27(4): 391-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23623247

RESUMEN

The impact of selenium (Se) in carcinogenesis is still debatable due to inconsistent results of observational studies, recent suspicion of diabetic side effects and e.g. dual roles of glutathione peroxidases (GPx). Previously, our group introduced long-term studies on lung carcinogenesis using the jaagtsiekte sheep retrovirus (JSRV) induced ovine pulmonary adenocarcinoma (OPA) as an innovative animal model. The present report describes the results of sufficient (0.2 mg Se/kg dry weight (dw)) vs. marginal (<0.05 mg Se/kg dw) nutritional Se supply on cancer progression over a two-year period in 16 animals. Computed tomography (CT) evaluation of lung cancer progression, final pathological examination, evidence of pro-viral JSRV-DNA in lung, lymph nodes and broncho-alveolar lavage cells as well as biochemical analysis of Se, GPx1 and thioredoxin reductase (TrxR) activity in lung tissue were recorded. Additionally, immunohistochemical determination of GPx1 expression in unaffected and neoplastic lung cells was implemented. The feeding regime caused significant differences in Se concentration and GPx1 activity in lung tissue between groups, whereas TrxR activity remained unaffected. JSRV was evident in broncho-alveolar lavage cells, lung tissue and lung lymph nodes. Quarterly executed CT could not demonstrate differences in lung cancer proliferation intensity. Necropsy and histopathology substantiated CT findings. Immunohistochemical analysis of GPx1 in lung tissue suggested a coherency of GPx1 immunolabelling intensity in dependence of tumour size. It was concluded that the model proved to be suitable for long-term studies of lung cancer proliferation including the impact of modifiable nutritional factors. Proliferation of OPA was unaffected by marginal vs. sufficient nutritional Se supply.


Asunto(s)
Suplementos Dietéticos , Pulmón/metabolismo , Reacción en Cadena de la Polimerasa , Adenomatosis Pulmonar Ovina/patología , Selenio/administración & dosificación , Selenio/metabolismo , Tomografía Computarizada por Rayos X , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Inmunohistoquímica , Pulmón/enzimología , Adenomatosis Pulmonar Ovina/genética , Adenomatosis Pulmonar Ovina/metabolismo , Selenio/deficiencia , Ovinos , Factores de Tiempo , Glutatión Peroxidasa GPX1
15.
J Comp Pathol ; 148(2-3): 139-47, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22878053

RESUMEN

Seven sheep with a histopathological diagnosis of pulmonary adenocarcinoma with extrathoracic metastases were included in this retrospective study aiming to describe the pathological findings and to establish their relationship with Jaagsiekte sheep retrovirus (JSRV). In order of frequency, extrathoracic metastases were found in the liver, kidneys, skeletal muscle, digestive tract, spleen, skin and adrenal glands. Intrathoracic metastases involved the chest wall, regional lymph nodes, diaphragm and heart. Immunohistochemistry and polymerase chain reaction allowed detection of JSRV-related protein and nucleic acid, respectively, in the extrathoracic tumours of all cases. It is concluded that extrathoracic metastases constitute a pathological event of ovine pulmonary adenocarcinoma and confirm the malignant character of this virus-induced neoplasia.


Asunto(s)
Retrovirus Ovino Jaagsiekte/patogenicidad , Neoplasias Renales/veterinaria , Neoplasias Hepáticas/veterinaria , Adenomatosis Pulmonar Ovina/patología , Adenomatosis Pulmonar Ovina/virología , Enfermedades de las Ovejas/patología , Enfermedades de las Ovejas/virología , Animales , Femenino , Retrovirus Ovino Jaagsiekte/aislamiento & purificación , Riñón/patología , Riñón/virología , Neoplasias Renales/secundario , Neoplasias Renales/virología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/virología , Pulmón/patología , Pulmón/virología , Masculino , Neoplasias de los Músculos/secundario , Neoplasias de los Músculos/veterinaria , Neoplasias de los Músculos/virología , Músculo Esquelético/patología , Músculo Esquelético/virología , Estudios Retrospectivos , Ovinos , Bazo/patología , Bazo/virología , Neoplasias del Bazo/secundario , Neoplasias del Bazo/veterinaria , Neoplasias del Bazo/virología
16.
Virus Genes ; 45(3): 508-17, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22864547

RESUMEN

Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer in sheep. A unique feature is that JSRV envelope protein is also the oncogene for this virus. Previous studies have identified the cytoplasmic tail (CT) of the envelope transmembrane (TM) protein as critical for transformation although other regions of Env have also been implicated. In this study, the roles of other Env regions in transformation were investigated. Chimeras between JSRV Env and the Env of a related non-oncogenic endogenous retrovirus (enJSRV, 5F16) were used. A chimera containing the membrane-spanning region (MSR) of enJSRV inserted into JSRV Env showed substantially reduced transformation, indicating that the MSR plays a role in transformation. Transformation by this chimera was highly dependent on both Ras/Raf/MEK/MAPK and PI3K/Akt/mTOR signaling. A chimera containing the two amino acids in the TM ectodomain that distinguish JSRV and enJSRV showed modestly reduced transformation. Chimeras in the SU protein indicated that the amino terminal region of SU contributes to transformation, while the C-terminal part is not important. To test if Env trimerization is important for transformation, we mutated a leucine-rich sequence in the putative trimerization domain in the ectodomain of TM (Tri-M). This mutant could not transform cells and it did not oligomerize. However, Tri-M could complement a non-transforming mutant CT mutant (Y590F) so oligomerization is not necessary for at least some aspects of transformation. These experiments provide new insight into the regions and residues of JSRV Env protein necessary for oncogenic transformation.


Asunto(s)
Transformación Celular Viral , Retrovirus Ovino Jaagsiekte/genética , Adenomatosis Pulmonar Ovina/virología , Proteínas del Envoltorio Viral/metabolismo , Animales , Electroforesis en Gel de Poliacrilamida , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Células HEK293 , Humanos , Retrovirus Ovino Jaagsiekte/metabolismo , Leucina/genética , Leucina/metabolismo , Ratones , Mutagénesis Sitio-Dirigida , Células 3T3 NIH , Plásmidos/genética , Plásmidos/metabolismo , Multimerización de Proteína , Estructura Terciaria de Proteína , Adenomatosis Pulmonar Ovina/patología , Ensayo de Radioinmunoprecipitación , Ovinos/virología , Relación Estructura-Actividad , Proteínas del Envoltorio Viral/genética
17.
PLoS One ; 7(7): e41965, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22911867

RESUMEN

The Jaagsiekte sheep retrovirus exJSRV and its endogenous counterpart enJSRV co-exist in sheep. exJSRV, a betaretrovirus, is the etiological agent of ovine pulmonary adenocarcinoma, and it has been demonstrated in vitro that an enJSRV Gag variant bearing the R-to-W amino acid change at position 21 was able to block exJSRV budding from the cells, providing a potential protective role for the host. In this work, we developed a fast mutation detection assay based on the oligo ligation assay (OLA) that permits the quantification of the relative proportions of the R21 and W21 Gag variants present in individual genomes and in cDNA obtained from normal and exJSRV-induced lung tumors. We have shown that the W21/R21 ratio is variable within and between breeds. We also describe for the first time that putative protecting enJSRV variants were expressed in alveolar type II cells (AECII), the major target of exJSRV.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Retrovirus Endógenos/genética , Regulación Viral de la Expresión Génica , Ovinos/virología , Animales , Secuencia de Bases , ADN de Neoplasias/aislamiento & purificación , Productos del Gen gag/genética , Genoma/genética , Endogamia , Retrovirus Ovino Jaagsiekte/genética , Pulmón/patología , Pulmón/virología , Datos de Secuencia Molecular , Proteínas Mutantes/genética , Mutación/genética , Provirus/genética , Adenomatosis Pulmonar Ovina/patología , Adenomatosis Pulmonar Ovina/virología , ARN Neoplásico/aislamiento & purificación , Reproducibilidad de los Resultados
18.
J Comp Pathol ; 147(4): 441-51, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22721818

RESUMEN

Ovine pulmonary adenomatosis (OPA), also known as jaagsiekte, is a transmissible beta retrovirus-induced lung tumour of sheep that has several features resembling human bronchoalveolar carcinoma (BAC). Angiogenesis has been suggested to be one of the most important factors underlying tumour growth and invasion. This process involves the action of growth factors including vascular endothelial growth factor (VEGF)-C, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-C and its receptor (PDGFR-α). Bovine lactoferrin (bLF), an iron and heparin-binding glycoprotein secreted into various biological fluids, has been implicated in innate immunity and has anti-inflammatory and anti-tumour functions. Tissues from 16 cases of OPA were compared with tissues from seven healthy control sheep by immunohistochemistry. Expression of the markers was assessed semi-quantitatively by ascribing an immunoreactivity score (IRS) with a maximum value of 300. VEGF-C, bFGF, PDGF-C, PDGFR-α and bLF signals were detected in 10/16, 15/16, 12/16, 15/16 and 10/16 of the OPA cases studied, respectively. bLF expression was weak in the neoplastic epithelial cells (IRS 21.4 ± 10.0) in contrast to high levels detected in infiltrating macrophages and plasma cells (IRS 141.3 ± 24.8 and 140.0 ± 25.1, respectively). The PDGFR-α IRS was elevated for neoplastic epithelial cells (108.9 ± 18.2) and was lowest for macrophages and plasma cells (20.4 ± 13.1 and 13.7 ± 12.4, respectively). These results suggest that bFGF, VEGF-C and PDGF-C have roles in the pathogenesis of OPA. bLF may activate macrophages and plasma cells in these lesions, but limited expression of bLF by neoplastic cells may be a consequence of defective or impaired function of this molecule.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lactoferrina/metabolismo , Neoplasias Pulmonares/veterinaria , Adenomatosis Pulmonar Ovina/metabolismo , Animales , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Inmunohistoquímica/veterinaria , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Linfocinas/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Adenomatosis Pulmonar Ovina/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Ovinos , Factor C de Crecimiento Endotelial Vascular/metabolismo
19.
Trop Anim Health Prod ; 43(8): 1611-5, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21626063

RESUMEN

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring retrovirus-induced transmissible lung cancer in sheep. Lungs and associated (bronchial and mediastinal) lymph nodes of seven sheep with OPA were examined. Lungs had few multifocal consolidated slightly elevated gray to white masses ranging from 0.5 to 3 cm in diameter. Histopathologically, these masses appeared as well-differentiated acinar adenocarcinoma with little evidence of anaplasia. The acini composed of well-differentiated cuboidal to low columnar epithelium with clear or vacuolated cytoplasm and low mitotic index. No metastases were observed in the bronchial and mediastinal lymph nodes of any animal. The presence of Jaagsiekte sheep retrovirus (JSRV) was demonstrated in the lungs by immunohistochemistry. JSRV protein was detected in all tumor epithelial cells, histologically normal alveolar type II cells, and few bronchiolar epithelial cells, alveolar macrophages, lymphocytes, and plasma cells. This study is the first to confirm the presence of natural OPA in Egypt.


Asunto(s)
Adenocarcinoma Bronquioloalveolar/veterinaria , Proteínas de la Cápside/metabolismo , Retrovirus Ovino Jaagsiekte/patogenicidad , Enfermedades Pulmonares/patología , Pulmón/metabolismo , Adenomatosis Pulmonar Ovina/patología , Proteínas de los Retroviridae/metabolismo , Células Acinares/metabolismo , Células Acinares/patología , Células Acinares/virología , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/virología , Animales , Antígenos Virales/metabolismo , Egipto , Células Epiteliales/metabolismo , Células Epiteliales/virología , Retrovirus Ovino Jaagsiekte/metabolismo , Pulmón/patología , Enfermedades Pulmonares/virología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Ganglios Linfáticos/virología , Linfocitos/metabolismo , Linfocitos/virología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Células Plasmáticas/metabolismo , Células Plasmáticas/virología , Adenomatosis Pulmonar Ovina/virología , Ovinos , Oveja Doméstica
20.
PLoS Pathog ; 7(3): e1002014, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21483485

RESUMEN

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.


Asunto(s)
Adenocarcinoma/veterinaria , Células Epiteliales Alveolares/virología , Transformación Celular Viral , Retrovirus Ovino Jaagsiekte/patogenicidad , Neoplasias Pulmonares/veterinaria , Adenomatosis Pulmonar Ovina/patología , Adenomatosis Pulmonar Ovina/virología , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Inflamación/inmunología , Pulmón/embriología , Neoplasias Pulmonares/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/virología , Ovinos , Proteínas Estructurales Virales/metabolismo
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