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

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

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.

Technical Summary

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.

Publications

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Description CVR Website Updated April 2015 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact In March 2015, we embarked on a project to update our website to include up to date information about our staff, research groups and current projects. During the later half of 2014, we filmed 'talking head' interviews of our Principal Investigators to be included on their research group pages, proving interactive and engaging content for our web pages and a valuable source of information for other researchers, stakeholders, target audiences and prospective employees.



We have received very positive feedback about the developments including both internally from CVR staff but also from other research centres within the University of Glasgow who have subsequently requested advice on how we have delivered the project.

We this is a positive step, which demonstrates that we are taking the lead in promoting the CVR as a World-class centre of science research.

New interactive and up to date content, also means that visitors to our pages, spend longer looking at content and therefore, this provides a better opportunity to share information.
Year(s) Of Engagement Activity 2015
URL http://www.cvr.ac.uk
 
Description Cafe Scientifique April 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact CVR scientists David Bhella and Gillian Slack gave a Cafe Scientifique in the Victorian bar of the Tron theatre. The subject was emerging viruses and the Ebola virus. David gave an overview of the causes of viral emergence and Gillian gave a personal account of her experiences working in Sierra Leone to help to bring the current Ebola outbreak under control. The talk was followed by a lively discussion covering such diverse topics as MMR, complementary medicines, endogenous retroviruses and the cultural impact of outbreaks such as Ebola and SARS.



None at present but it is anticipated that we would make plans for further future related activity or get involved in another Cafe Scientifique event with new presenters and cover different topics.
Year(s) Of Engagement Activity 2015
URL https://www.facebook.com/centreforvirusresearch
 
Description November 2016 - CVR Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact In December 2016, we published the CVR internal newsletter to give staff and students an overview of the centre's activities and news stories. The newsletter is circulated around our full centre distribution list and also shared with communications colleagues in MVLS and III along with MRC stakeholders.
Year(s) Of Engagement Activity 2016
URL https://www.facebook.com/centreforvirusresearch
 
Description TWIV 188 - Podcast June 2012 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Vincent Racaniello visited the CVR in 2012 to interview some of our researchers about their work in Hepatitis C virusand jaagsiekte sheep retrovirus.

The TWIV podcast is incredibly popular with followers throughout the World. This allowed us to share information about the CVR and our research to a large, digital audience.

Vincent Racaniello has since returned to work with the CVR on further podcasts. The podcast also sparked online comments and questions.
Year(s) Of Engagement Activity 2012
URL https://www.facebook.com/centreforvirusresearch