Suppression of host protein synthesis and regulation of interferon response by PRRS virus

Host innate immune system produces cytokines and chemokines in response to viral infection for protection. Type I interferons (IFN-α/β) are antiviral cytokines that play a major role during the early stage of infection, and have been shown to inhibit PRRSV replication. Thus, such cytokines are ideal targets for PRRSV to disarm and escape the host immune surveillance. Indeed, poor induction of proinflammatory cytokines and type I IFNs has been shown as the hallmark of PRRS virus in cells and pigs. Viral IFN antagonists have been identified for PRRSV, and the nsp1 protein is a potent suppresser for IFN production. The objective of this study was to identify and characterize the molecular basis of the PRRS virus nsp1 protein-mediated innate immune modulation.

PRRSV nsp1 gene was subcloned to produce nsp1-alpha and nsp1-beta two subunits. Each subunit protein was expressed in cells, and the modulation of IFN production was examined by reporter and bioassays. Host protein synthesis was determined by immunofluorescent microscopy and western blot, and host mRNA nuclear transport was determined by in situ hybridization using an oligo (dT) probe.

The nsp1β protein was identified as the viral IFN antagonist that played the role for blocking host mRNA nuclear export. Blocking host mRNA nuclear export was determined to be common for different strains of PRRSV and was also identified for both North American genotype and European genotypes. The inhibition of host mRNA nuclear export resulted in the suppression of host protein synthesis and was correlated to the suppression of IFN production and other antiviral proteins. This is a novel mechanism for host innate immune modulation and evasion by PRRSV.

PRRSV has the ability to escape the host innate immunity, and nsp1 is a potent viral antagonist suppressing the IFN production during infection. The nsp1α subunit of nsp1 is known to inhibit the formation of IFN enhanceosome, and in the present study, we show that the nsp1β subunit inhibits the host mRNA nuclear export and thus suppresses the production of IFNs and other antiviral proteins.

Disclosure of Interest: None Declared.