The A3 gene of Alcelaphine herpesvirus 1 encodes a viral semaphorin that is non-essential for the induction of malignant catarrhal fever

Abstract

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-Herpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species transmitted to a variety of ruminant susceptible species. Wildebeest-derived (WD)-MCF is a frequently fatal lymphoproliferative and degenerative disease of ruminants. Experimentally, WD-MCF can be reproduced in rabbits. The A3 open reading frame (ORF) of the AlHV-1 encodes a putative semaphorin homolog protein, thereafter named AlHV-sema. Semaphorins are secreted and membrane-associated proteins characterized by a conserved amino-terminal ‘Sema’ domain. Initially identified as guidance factors that assist axons pathfinding during neural development, semaphorins have been shown over the last decade to have significant functions in various processes of immunoregulation. Bioinformatics analyses revealed that AlHV-sema has a high homology to the cellular Sema7A. Besides its roles in neural development, Sema7A has been shown to play pivotal functions in the regulation of cytokine secretion and as a tumor suppressor. In order to investigate whether AlHV-Sema could play a role in the pathogenesis of WD-MCF, we used the AlHV-1 BAC clone and produced a strain deleted for A3 and a revertant strain. The strain deleted for A3 replicated comparably to the wild-type parental strain in vitro. In vivo, rabbits infected with the strain deleted for A3 developed WD-MCF similarly to that observed with the parental strain with both severely increased CD8+ T cell frequencies and viral genomic charge over time in peripheral blood and in lymph nodes at time of death, as well as indistinguishable histopathological lesions in lymphoid organs and in liver, lung and kidney. In conclusion, this study demonstrates that AlHV-sema is not essential for the induction of WD-MCF in rabbits