Abstract
Enzootic nasal adenocarcinoma (ENA) is a contagious neoplasm of the secretory epithelial cells of the nasal mucosa of sheep and goats. It is associated with the betaretrovirus, enzootic nasal tumor virus (ENTV), but a causative relationship has yet to be demonstrated. In this study, 14-day-old lambs were experimentally infected via nebulization with cell-free tumor filtrates derived from naturally occurring cases of ENA. At 12 weeks post-infection (wpi), one of the five infected lambs developed clinical signs, including continuous nasal discharge and open mouth breathing, and was euthanized. Necropsy revealed the presence of a large bilateral tumor occupying the nasal cavity. At 45 wpi, when the study was terminated, none of the remaining infected sheep showed evidence of tumors either by computed tomography or post-mortem examination. ENTV-1 proviral DNA was detected in the nose, lung, spleen, liver and kidney of the animal with experimentally induced ENA, however there was no evidence of viral protein expression in tissues other than the nose. Density gradient analysis of virus particles purified from the experimentally induced nasal tumor revealed a peak reverse transcriptase (RT) activity at a buoyant density of 1.22 g/mL which was higher than the 1.18 g/mL density of peak RT activity of virus purified from naturally induced ENA. While the 1.22 g/mL fraction contained primarily immature unprocessed virus particles, mature virus particles with a similar morphology to naturally occurring ENA could be identified by electron microscopy. Full-length sequence analysis of the ENTV-1 genome from the experimentally induced tumor revealed very few nucleotide changes relative to the original inoculum with only one conservative amino acid change. Taken together, these results demonstrate that ENTV-1 is associated with transmissible ENA in sheep and that under experimental conditions, lethal tumors are capable of developing in as little as 12 wpi demonstrating the acutely oncogenic nature of this ovine betaretrovirus.
Highlights
Enzootic nasal adenocarcinoma (ENA) is a neoplasm of the secretory epithelial cells of the nose of sheep and goats [1]
enzootic nasal tumor virus (ENTV)-1 was detected in the ENA inoculum by reverse transcriptase (RT) activity (Figure 1A) and by immunoblot analysis with antibodies specific for ovine betaretroviral envelope and capsid proteins (Figure 1B)
These results confirmed the presence of ENTV-1 antigen and reverse transcriptase activity in the inoculum
Summary
Enzootic nasal adenocarcinoma (ENA) is a neoplasm of the secretory epithelial cells of the nose of sheep and goats [1]. No metastasis has been reported in ENA cases, but disruption of the nasal septum structure as well as erosion of the cribiform plate has been reported [2,3]. Due to the cell type transformed and the space occupying nature of the tumor, the clinical signs of ENA include production of copious nasal exudate, open mouth breathing, dyspnea and facial asymmetry [1]. A neoplasm of the secretory epithelial cells of the distal lung of sheep, called intranasal inoculation of newborn goat kids with clarified nasal exudates pooled from three ENA affected goats [11]. In 1953, Cohrs reported transmission of ENA in sheep using cell and bacteria-free tumor filtrate [12], but more recently, similar experiments attempting transmission of ENA in sheep were unsuccessful (Dr James DeMartini, personal communication)
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