Molecular Pathogenesis of Ovine Pulmonary Adenocarcinoma: Host Genetics and Age as Determinants of Disease Progression

Ovine pulmonary adenocarcinoma (OPA) is a lung tumour of sheep caused by a virus known as Jaagsiekte sheep retrovirus (JSRV). OPA is one of the most important viral diseases of this animal species in the United Kingdom and Europe (OPA was for example the cause of death of Dolly, the first large mammal cloned). JSRV induces lung tumour by the expression of one of its proteins (the envelope) that stimulates some cells in the lungs, called type II pneumocytes and Clara cells, to proliferate without control. JSRV belongs to a family of viruses known as retroviruses. JSRV is transmitted from infected to uninfected host horizontally as any other virus (e.g. flu virus) and is therefore called an 'exogenous' retrovirus. Interestingly, sheep have also 'endogenous' retroviruses in their DNA. This is because retroviruses, during their life cycle, insert their genetic material in the cell's own DNA. During evolution, some retroviruses have colonized the DNA of all animal species where they co-exist with normal genes. Endogenous retroviruses are in general 'benign' viruses that do not cause any harm. Thus, sheep can be infected by a harmful 'exogenous' virus (JSRV) and at the same time they have ~27 different endogenous 'benign' viruses (enJSRVs) in their genome that are highly related to JSRV. enJSRVs can protect sheep against JSRV infection by blocking the replication of the latter. Interestingly, we have recently discovered that at least 8 of the 27 enJSRVs viruses are present only in some sheep/ sheep breeds. In this proposal we will study why infection with JSRV leads to tumor in some sheep but not in others. Our hypothesis is that (i) lambs are most susceptible to OPA because their lung cells can be infected more easily by JSRV and (ii) that the presence of benign enJSRVs in some sheep protects them against the virulent JSRV. By completing the proposed work we will be able to transfer our findings into practice by offering flock management advice on the most susceptible animals to JSRV infection and disease progression. Thus, this proposal is highly relevant to BBSRC strategy and will improve the sustainability of the UK farming system.

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by a retrovirus known as Jaagsiekte sheep retrovirus (JSRV). We believe that several factors governing the interplay between JSRV and its host set OPA apart from the totality of infectious diseases of domestic animals. JSRV has a structural protein (the envelope) that is a dominant oncoprotein and whose sole expression is sufficient to induce cell transformation in vitro and in vivo. Most interestingly, ~27 endogenous viruses highly related to JSRV are present within the sheep genome, are transcriptionally active, can interfere with JSRV replication at different level of the replication cycle and evolved to be absolutely necessary for sheep reproductive biology. We have recently discovered that at least 8 enJSRV loci that have the potential to block JSRV replication are highly polymorphic in the sheep population. Our working hypothesis is that age at time of infection and genetic background of the host influence the outcome (inapparent infection vs. clinical disease) of JSRV infection. We will test our hypothesis by investigating (i) the evolutionary history of insertionally polymorphic enJSRV proviruses; (ii) the association of enJSRV polymorphisms with resistance to OPA and (iii) determining whether susceptibility of young animals to OPA is directly correlated with cell cycle status and infection of type II pneumocytes/Clara cells, the target cells of transformation. By understanding the nature of the interaction between JSRV/enJSRVs and their host we will help to dissect the molecular pathogenesis of OPA but we will also have the opportunity to dissect retrovirus-host coevolution in a unique model system. In addition, the completion of this proposal will help to improve the sustainability of the UK farming system by offering flock management advice on the most susceptible animals to JSRV infection and disease progression.