Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain

Authors: FERNANDEZ-SAINZ, IGNACIO - University Of Connecticut; Zhu, James; O'DONNELL, VIVIAN - University Of Connecticut; Diaz San Segundo, Fayna; VELAZQUEZ, LAURO - Oak Ridge Institute For Science And Education (ORISE); De Los Santos, Teresa; Borca, Manuel

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/2015
Publication Date: 5/21/2015
Publication URL: http://handle.nal.usda.gov/10113/61570
Citation: Fernandez-Sainz, I., Zhu, J.J., O'Donnell, V., Diaz San Segundo, F.C., Velazquez, L., De Los Santos, T.B., Borca, M.V. 2015. Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain. Virology. 483:284-290. DOI: 10.1016/j.virol.2015.04.024.

Interpretive Summary: Interferon (IFN) is one of the mechanisms used by humans and animals to control virus infections. In humans it is used for treatment of various disease conditions including hepatitis C infections and some types of cancer. Currently, there is no information regarding the effect of IFN therapy in infection with Classical swine fever virus (CSFV) in swine. Here, we report the effect of IFN treatment in swine experimentally infected a highly virulent CSFV strain called Brescia. IFN treatment delayed the appearance of clinical signs and virus replication in the infected animals although it did not prevent lethal disease. This is the first report describing the effect of IFN treatment during CSFV infection in swine.

Technical Abstract: Classical swine fever (CSF) is an economically significant, highly contagious swine disease. The etiological agent, CSF virus (CSFV), is an enveloped virus with a positive-sense, single-stranded RNA genome, classified as a member of the genus Pestivirus within the family Flaviviridae (Becher et al., 2003). The 12.5 kb CSFV genome contains a single open reading frame that encodes a 3898-amino acid polyprotein and ultimately yields 11 to 12 final cleavage products (NH2-N^pro-C-E^rns-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH) through co- and post-translational processing of the polyprotein by cellular and viral proteases (Rice, 1996). Prophylactic vaccination with live attenuated viruses (LAVs) can induce effective protection against CSF, often earlier than protection afforded by the adaptive immune response (van Oirschot, 2003); however, the host mechanisms mediating this innate response remain unknown. The ability of the host’s innate immune system to interact with CSFV replication has been studied in vitro by several groups (Bensaude et al., 2004; Choi et al., 2004; Dong et at., 2013; Fernandez-Sainz et al., 2010), and included evaluation of the inhibitory effects induced by IFN (Hi et al., 2014). It has been reported that CSFV possesses mechanisms that hinder the induction and production of IFNs during infection. This inhibitory effect has been associated with two viral non-structural proteins, NS3A and N^pro. For instance, the dsRNA-binding and RNase activities of pestivirus E^rns has been shown to inhibit IFN synthesis induced by extracellular dsRNA (Magkouras et al., 2008) and/or pestiviral single- and double-stranded RNAs (Iqbal et al., 2004; Luo et al., 2009; Matzener et al., 2009). In addition, IFN regulatory factor 7 (IRF7) is deregulated by directly interacting with CSFV N^pro, thus inhibiting the production of IFN-alpha and decreasing the anti-viral cellular response (Fiebach et al., 2011). Also, N^pro promotes proteosomal degradation of IFN regulatory factor 3 (IRF3) (Bauhofer et al., 2007; La Rocca et al., 2005; Seago et al., 2007) and recombinant CSFV lacking N^pro is attenuated in swine (Mayer et al., 2004). However, replacement of N^pro in a virulent CSFV strain by the corresponding gene of an attenuated strain does not diminish the virulent phenotype (Mayer et al., 2004). Moreover, recombinant viruses harboring N^pro mutations abrogating the ability to degrade IRF3 and thus preventing IFN-alpha/Beta induction were not attenuated in swine (Ruggli et al., 2009). Therefore, the actual role of IFN during CSFV infection in swine is poorly understood. Here, we report the effect of IFN-alpha treatment (delivered by a replication defective human adenovirus type 5, Ad5) on the course of experimental infection of swine infected with the highly virulent CSFV Brescia strain. Our results show that IFN-alpha treatment significantly delays the appearance of CSF disease and systemic virus replication. To our knowledge, this is the first report describing the effect of IFN-alpha during CSFV infection in swine.