ABSTRACT
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.
INTRODUCTION
Ovine pulmonary adenocarcinoma (OPA) is an infectious lung disease of sheep that is a significant economic problem and welfare concern for sheep producers in many countries (1, 2). The main clinical features of OPA are loss of condition and respiratory distress, and in many advanced cases, there is an accumulation of fluid in the lungs that drains from the sheep’s nostrils when its head is lowered (3). Lung function is often further compromised by the presence of bacterial or parasitic coinfection (1). By the time that clinical signs become apparent, tumor growth is typically extensive, and the disease is invariably fatal.
OPA is caused by jaagsiekte sheep retrovirus (JSRV), an exogenous betaretrovirus (4). Despite its etiological role in OPA, infected sheep produce only a limited adaptive immune response to JSRV antigens, and this has precluded the development of an effective preclinical serological diagnostic test or vaccine to control the spread of the disease (2). The mechanism underlying the poor immune responsiveness of sheep