Npro His49 and Erns Lys412 mutations in pig bovine viral diarrhea virus type 2 synergistically enhance the cellular antiviral response.

Type I interferons are major components of the innate immune response of hosts, and accordingly, many viruses have evolved mechanisms to modulate the host response during infection. Bovine viral diarrhea virus (BVDV) nonstructural protein Npro and structural protein Erns play important roles in inhibiting type I interferon. The aim of this study was to explore the epistatic effects of amino acid mutations in Npro and Erns in porcine ST cells to characterize the immune response induced by BVDV-2. Plasmids with mutant amino acids His49 (H49), Glu22 (E22) in Npro, and His300 (H300), Lys412 (K412) in Erns which had been changed to Alanine (A) had similar effects on type I interferon production in MDBK and ST cells, but resulted in much greater ISG15, OAS, and Mx production in ST cells. The rescued vASH/NproH49ErnsK412 virus showed the best efficiency with respect to modulating antiviral cytokines, indicating that the amino acids Npro H49 and Erns K412 had highly synergistic effects in abolishing the ability to inhibit type I interferon. These findings have importance practical implications owing to the increasing prevalence of BVDV infections, including persistent infections, in domestic pigs.