The A2 gene of alcelaphine herpesvirus-1 is a transcriptional regulator affecting cytotoxicity in virus-infected T cells but is not required for malignant catarrhal fever induction in rabbits

Parameswaran, Nevi; Haig, David; Dewals, Benjamin G.; Giles, Tom C.; Deppmann, Christopher; Blythe, Martin; Vanderplasschen, Alain; Emes, Richard D.

Abstract

Alcelaphine herpesvirus-1 (AlHV-1) causes malignant catarrhal fever (MCF). The A2 gene of AlHV-1 is a member of the bZIP transcription factor family. We wished to determine whether A2 is a virulence gene or not and whether it is involved in pathogenesis by interference with host transcription pathways. An A2 gene knockout (A2?AlHV-1) virus, revertant (A2revAlHV-1) virus, and wild-type virus (wtAlHV-1) were used to infect three groups of rabbits. A2?AlHV-1-infected rabbits succumbed to MCF, albeit with a delayed onset compared to the control groups, so A2 is not a critical virulence factor. Differential gene transcription analysis by RNAseq and qRT-PCR validation of a selection of these was performed in infected large granular lymphocyte (LGL) T cells obtained in culture from the MCF-affected animals. A2 was involved in the transcriptional regulation of immunological, cell cycle and apoptosis pathways. In particular, there was a bias towards ?? T cell receptor (TCR) expression and downregulation of ?? TCR. TCR signalling, apoptosis, cell cycle, IFN-? and NFAT pathways were affected. Of particular interest was partial inhibition of the cytotoxicity-associated pathways involving perforin and the granzymes A and B in the A2?AlHV-1-infected LGLs compared to controls. In functional assays, A2?AlHV-1-infected LGLs were significantly less cytotoxic than wtAlHV-1- and A2revAlHV-1-infected LGLs using rabbit corneal epithelial cells (SIRC) as targets. This implies that A2 is involved in a pathway enhancing the expression of LGL cytotoxicity. This is important as virus-infected T cell cytotoxicity in vivo has been suggested as a potential mechanism of disease induction in MCF.

• Journal Article Type: Article
• Acceptance Date: Apr 13, 2014
• Publication Date: Aug 8, 2014
• Deposit Date: Oct 16, 2017
• Electronic ISSN: 1872-7492
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 188
• Pages: 68-80
• DOI: https://doi.org/10.1016/j.virusres.2014.04.003
• Public URL: https://nottingham-repository.worktribe.com/output/1116187
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S016817021400152X
• PMID: 00033912
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