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Expression of the NS3 protease of cytopathogenic BVDV results in the induction of apoptosis but does not block activation of the interferon beta promoter

¹ University of Leeds;
² Division of Virology, National Institute for Medical Research, Mill HIll

³ E-mail: a.macdonald{at}leeds.ac.uk

The Pestivirus, Bovine Viral Diarrhoea Virus (BVDV), can exist as two biotypes, cytopathogenic (cp) and non-cytopathogenic (ncp). The cp differs from ncp by the continual expression of free non-structural protein 3 (NS3). Cp BVDV infection of cultured cells induces apoptosis, whereas ncp BVDV infection has been reported to block the induction of IFN-β. To investigate the viral mechanisms underlying these effects NS3 or NS2-3 proteins of ncp and cp BVDV biotypes, together with the cognate NS3 cofactor NS4A, were expressed in cells and their effect upon apoptosis and induction of IFN-β was investigated. Expression of NS3/4A resulted in increased activity of caspase 9 and caspase 3, indicating the induction of the intrinsic apoptosis pathway. Mutational analysis revealed that a protease inactive NS3/4A was unable to induce apoptosis suggesting that the NS3 protease activity is required for initiation of apoptosis during cp BVDV infection. The ability of NS2-3 to modulate activation of the IFN-β promoter was also investigated. These studies confirmed that, unlike the related viruses HCV and GBV-B, the BVDV proteases are unable to inhibit TLR3 and RIG-I dependent activation of the IFNβ promoter. These data suggest that BVDV NS3/4A is responsible for regulating the levels of cellular apoptosis and provide new insights regarding the viral elements associated with cp biotype pathogenesis.

Received 26 August 2009; accepted 25 September 2009.