Virus-host interactions in an ovine model of lung cancer

Szafran, Bartosz (2014) Virus-host interactions in an ovine model of lung cancer. PhD thesis, University of Glasgow.

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Abstract

Ovine pulmonary adenocarcinoma (OPA) is a respiratory disease caused by jaagsiekte sheep retrovirus (JSRV). This virus induces the growth of large lung tumours in affected sheep and is a significant problem for the sheep industry. An interesting feature of OPA is that it occurs only in sheep. Goats may also be infected by JSRV but disease progression is limited to the early stages so that clinical signs do not develop. The ability of a virus to replicate in its host is dependent on a wide range of cellular proteins, including essential, required (‘dependency’) factors, and proteins that act to inhibit replication, referred to as restriction factors. Greater understanding of the roles of dependency and restriction factors can provide insights into pathogenesis and the species-specificity of infection.

The aim of this study was to investigate the potential role of previously identified restriction factors on the replication of JSRV, and specifically whether APOBEC3 or TRIM5 proteins are responsible for the specificity of OPA for sheep. To examine this question, ruminant genes for APOBEC3 were cloned and their activity against JSRV was tested using a replication-defective reporter virus that expresses GFP. This system allows the activity of putative restriction factors to be measured quantitatively by flow cytometry. These experiments revealed that ruminant APOBEC3 proteins, including those from sheep, inhibit JSRV infection in vitro. Further analysis of the mechanism of restriction of JSRV by sheep APOBEC3 provided evidence for cytidine deaminase-dependent and independent mechanisms against this virus.

In order to extend the studies on the species-specificity of APOBEC, several human and mouse APOBEC proteins were analysed for their activity against JSRV. Murine APOBEC3 and human APOBEC3F were both able to restrict JSRV in vitro, while other human APOBECs tested were not. These results have impact for the development of murine model of OPA and for the development of JSRV as a gene delivery vector.

To assess the impact of TRIM5 on JSRV replication, derivatives of the permissive cell line CRFK were created that stably express TRIM5 from a range of ruminant and primate species. Infection studies performed in cell culture indicated that none of the TRIM5 proteins tested restrict JSRV, at least during the early stages of virus infection. Further studies are needed to examine other potential mechanisms of activity of TRIM5 against JSRV.

This thesis has revealed new insights into host-pathogen interactions in OPA that may contribute to the development of control strategies against this disease. In addition, these data provide a background for the future development of JSRV as a gene delivery vector.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: JSRV, jaagsiekte sheep retrovirus, OPA, ovine pulmonary adenocarcinoma, lung cancer, restriction factors, APOBEC, TRIM, species-specificity, virus-host interactions, model of lung cancer.
Subjects: Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: Griffiths, Dr. D. and Cousens, C. and Palmarini, Prof. M.
Date of Award: 2014
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:2014-6142
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 20 Feb 2015 09:06
Last Modified: 21 Feb 2018 14:26
URI: http://theses.gla.ac.uk/id/eprint/6142

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