An I kappa B homolog encoded by African swine fever virus provides a novel mechanism for downregulation of proinflammatory cytokine responses in host macrophages

Cytokines stimulate inflammatory defenses against viral infections, In order to evade host defenses, viruses have developed strategies to counteract antiviral cytokines, African swine fever virus (ASFV) is a large, double-stranded DNA virus that infects macrophages. This study demonstrates that ASFV effectively inhibited phorbol myristic acid-induced synthesis of antiviral, proinflammatory cytokines alpha interferon, tumor necrosis factor alpha, and interleukin-8 in infected macrophages as assessed by enzyme-linked immunosorbent assay and reverse transcriptase PCR, In contrast, levels of mRNA and protein for transforming growth factor beta, an anti-inflammatory cytokine, were increased by ASFV infection, suggesting that ASFV-induced inhibition of cytokine synthesis mag be limited to cytokines activated by NF kappa B, An interleukin-8 promoter, containing an NF kappa B enhancer site, driving expression of a luciferase reporter gene was used to show that NF kappa B-dependent transcription was inhibited by the virus and by a cloned ASFV gene, A238L. This gene encodes a protein with homology to I kappa B, the inhibitor of NF kappa B. Electrophoretic mobility shift assay showed that cells expressing the A238L gene inhibited NF kappa B binding to DNA, These results suggest that the A238L gene product interacts with NF kappa B to prevent transcription and downregulate proinflammatory cytokine production, This novel viral evasion strategy encoded in a single I kappa B-like protein may be capable of inhibiting most macrophage NF kappa B-dependent antiviral mechanisms and may provide insights into how ASFV causes a fatal hemorrhagic disease of domestic pigs and a persistent infection in the African warthog, which is its natural permissive host.