The molecular basis of malignant catarrhal fever

Abstract

Alcelaphine herpesvirus-1 (A1HV-1) is gammaherpesvirus that can cause the devastating, fatal disease malignant catarrhal fever (MCF) in susceptible ruminant hosts but not in its natural host the blue wildebeest. Despite its scientific and economic importance little is known about the underlying molecular basis of MCF pathogenesis. The purpose of this study is to characterise four unique open reading frames (ORFs) of A1HV-1 and examine their contribution to viral pathogenesis. These ORFs are located at the left hand end of the genome, a region known to contain unique transforming and immunomodulatory genes in other gammaherpesviruses, and are predicted to encode two small gene products with no significant homology to any known proteins (ORF A1 and ORF A4), a transcription factor (ORF A2) and a member of the semaphorin family (ORF A3).A 6.2 Kb fragment from A1F1V-1 containing all four ORFs under their natural promoters was cloned into the left hand end region of murine gammaherpesvirus-76 (MHV-76). This allowed for the study of the in vivo contribution to pathogenesis of the gene products in a well characterised small animal model. The recombinant virus showed no difference in its ability to replicate in vitro. Viral titres and lung pathology in infected mice were also comparable although the A1HV-1 gene transcripts were detectable.The ORF A2 gene product expressed as a recombinant fusion protein in mammalian cells consistently showed nuclear localisation, supporting the prediction that this protein functions as a transcription factor. However, attempts to conclusively demonstrate transcriptional activity of this protein were unsuccessful.