City Research Online

Abstract

Classical swine fever virus (CSFV) is the causative agent of classical swine fever, a notifiable disease of economic importance that causes severe leukopenia, fever and haemorrhagic disease in domesticated pigs and wild boar across the globe. In vitro CSFV has been shown to antagonise the induction of type I IFN, partly through a function of its N-terminal protease (Npro) which binds IRF3 and targets it for proteasomal degradation. Additionally, Npro has been shown to antagonise apoptosis triggered by the dsRNA-homolog poly(I:C), however the exact mechanism by which this is achieved has not been fully elucidated.

The ability of Npro to inhibit poly(I:C)-mediated apoptosis was confirmed and in addition Npro was found to antagonise Sendai virus-mediated apoptosis in PK-15 cells. Gene edited PK-15 cell lines were used to show the dsRNA-sensing pattern recognition receptors (PRRs) TLR3 and RIG-I specifically recognise poly(I:C) and SeV respectively, subsequently triggering apoptosis through pathways that converge on IRF3 and culminate in the cleavage of caspase-3. Deletion of IRF3, stable expression of Npro and infection with wild-type CSFV were found to antagonise the mitochondrial relocalisation of Bax, a pro-apoptotic Bcl-2 family protein. Together, these findings show that the putative interaction between Npro and IRF3 is involved not only in its antagonism of type I IFN, but also dsRNA-mediated mitochondrial apoptosis. Elucidation of the mechanism by which Npro antagonises the apoptotic response will help inform the development of novel antivirals and rationally designed, live attenuated vaccines.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QL Zoology Q Science > QR Microbiology Q Science > QR Microbiology > QR180 Immunology Q Science > QR Microbiology > QR355 Virology R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine S Agriculture > SF Animal culture
Departments:	School of Health & Medical Sciences > Infection and Immunity Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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