Mechanisms of action of an African swine fever virus virulence factor

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The African swine fever virus-encoded protein DP71L, (also designated l14L, NL, 23NL) shares a conserved domain with the Herpes simplex virus encoded neurovirulence factor ICP34.5 and the host GADD34 protein. The DP71L protein is of great interest because it can act as a virulence factor in domestic pigs, and recently we have characterised two functions for the DP71L protein which may be important for virulence and evasion of host defences. The first of these functions involves activation of the serine/threonine protein phosphatase PP1. The second is inhibition of transcription from the IFNbeta promoter. Possibly these two activities are linked. Our data also show that DP71L inhibits NF-kB-dependent transcription activated by TNF-alpha. Thus DP71L may have a broader effect on host gene transcription than inhibiting IFN. The objectives of this project are: (1). To investigate the mechanism by which the DP71L protein causes a) activation of the PP1 phosphatase, b) inhibition of transcription of type I IFN; (2). To investigate if DP71L expression affects transcription of additional immunomodulatory genes; (3). To investigate the consequences of these activities of DP71L on virus replication, macrophage function and pathogenesis in pigs. These studies will reveal a novel mechanism for regulating IFN gene transcription as well as novel roles for PP1.

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