Ovine pulmonary adenocarcinoma (OPA) is a chronic respiratory disease of adult sheep caused by Jaagsiekte sheep retrovirus (JSRV). The primary route of disease transmission is by inhalation of the virus, which then infects respiratory epithelial cells initiating oncogenesis and tumour growth. Clinical signs are seen towards end stage disease and include laboured breathing and weight loss. In these animals, the production of copious amounts of virus rich fluid which pours from the nose when the hind legs are lifted is a common finding and pathognomic for OPA. Once these signs are apparent, the disease is invariably fatal. The worldwide prevalence of OPA has both economic and welfare implications. However, there is currently no effective preclinical test or vaccine to control spread of disease. This is primarily due to the lack of detectable immunological response at any stage of disease pathogenesis. Theories of central and peripheral tolerance have been proposed as explanations for this. OPA is also regarded as a potential model for human lung cancer. As in sheep, clinical presentation in humans is not until tumour growth is extensive by which time treatment is unsuccessful. This makes it difficult to study the initial stages of disease, and identify potential markers for early detection or targets for therapeutics. The aim of this study was to investigate these previously unexplored early stages of disease pathogenesis for OPA. The primary areas of interest were identification of the target cells for JSRV infection in the lung and analysis of the innate response following this infection. Samples for analysis were provided by the intratracheal inoculation of specific pathogen free lambs with an infectious molecular clone JSRV[21]. Lambs were euthanased 3, 10 and 72-91 days following inoculation and lung samples representing different stages of disease pathogenesis were collected from each lamb. Mock infected and non infected lambs were included as negative controls at each time point. Immunohistochemistry was used to localise virus expression to specific epithelial cell types within the ovine respiratory tract. The same techniques also offered a means of studying the postnatal development of the ovine respiratory tract. The innate response to infection and subsequent tumour growth was measured in terms of cytokine production. RNA was extracted from adjacent samples to those used for IHC, and qRTPCR measured mRNA levels of a number of inflammatory cytokines and chemokines at each time point. Immunohistochemical analysis of the ovine respiratory tract found evidence of cytodifferentiation during postnatal development. This has implications for the susceptibility of lambs to infectious and noxious insults during this period. JSRV was found to target multiple cell types in the ovine lung. These included Clara cells, type II pneumocytes and cells which did not express either of these mature markers. Analysis of cytokine expression in lung tissue both before and during JSRV expression and tumour growth found little evidence of a host response to virus expression. Changes in the levels of cytokine mRNA were detected for those primarily involved in tumour growth and survival. These included IL-8 and IDO, both of which have been found to be increased in some cases of human of lung tumour. These findings increase the understanding of the pathogenesis of OPA, and improve its validity as an animal model for human lung cancer
