Characterization of immunostimulatory components of orf virus (parapoxvirus ovis)

Abstract

Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-c that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.

Effect of ORF119 gene deletion on the replication and virulence of orf virus

“…Prevention and control of the disease cannot only improve the economic efficiency in sheep industry, but also has important public health implications. Although whole genome sequences for four strains of ORFV (OV-SA00, OV-IA82, NZ2 and D1701) have been deposited in the GenBank, functions of many genes are still poorly understood (Delhon et al, 2004;Friebe et al, 2011). Comparison of the whole genome sequence of sheep ORFV isolate (OVIA82) and goat isolate (OV-SA00) with bovine papular stomatitis virus isolate indicated that ORFV contained 132-134 ORFs (Delhon et al, 2004).…”

“…Comparison of the whole genome sequence of sheep ORFV isolate (OVIA82) and goat isolate (OV-SA00) with bovine papular stomatitis virus isolate indicated that ORFV contained 132-134 ORFs (Delhon et al, 2004). Furthermore, virulence and immune regulation-related genes were concentrated at the terminal inverted repeats (ITRs) region of the ORFV genome (Haig and Fleming, 1999;McInnes et al, 2001;Friebe et al, 2011). At present, only some ORFV virulence factors have been confirmed, which include viral interferon inhibitory protein (OVIFN, ORF020) , chemokine binding protein (CBP, ORF112) (Seet et al, 2003), GM-CSF/IL-2 inhibitory factor (GIF, ORF117) (Deane et al, 2000), viral interleukin 10 (VIL-10, ORF127) (Fleming et al, 1997;Chan et al, 2006) and vascular endothelial growth factor (VEGF, ORF132) (Lyttle et al, 1994;Savory et al, 2000).…”

Inactivated Parapoxvirus ovis induces a transient increase in the expression of proinflammatory, Th1-related, and autoregulatory cytokines in mice

“…Immune modulation by iPPVO has been investigated in several systems and was primarily associated with stimulation of a broad range of cytokines, including proinflammatory and Th1- and Th2-related cytokines (29). This complex cytokine response is also associated with the activation of several cell populations, including monocytes and Th1-like cells, human neutrophils, canine monocytes, and murine bone marrow-derived dendritic cells (BMDCs), among others (13,15-18,29,30). Most of these studies focused on in vitro stimulation of specific cell populations by preparations of iPPVO.…”

A New Rabies Vaccine Based on a Recombinant Orf Virus (Parapoxvirus) Expressing the Rabies Virus Glycoprotein

“…The short-term vector-specific immunity and the lack of serum antibodies efficiently neutralizing ORFV (38,40) enable repeated immunizations with the same or with different ORFV recombinants. Unique immune-modulating properties of ORFV strongly stimulate the innate immunity (40)(41)(42)(43) and rapidly generate foreign antigen-specific immune responses (44)(45)(46)(47). The apathogenic, Vero cell culture-adapted ORFV strain D1701-V is used to generate recombinants by substituting the viral vegf-e gene with a foreign gene, which thereby removes an ORFV virulence gene and leads to further attenuation (38,44,48).…”