Modified vaccinia Ankara (MVA) is an attenuated vaccinia virus, and is a promising vaccine vector for variola and monkeypox viruses, as well as for other pathogens. The MVA determinants important for vaccine efficacy and immunogenicity are poorly defined. MVA infection of fibroblast cells activates NF-κB, a characteristic not ascribed to wild-type vaccinia viruses. Thus, NF-κB activation, and the subsequent upregulation of host immune molecules, could be one of the determinants for MVA's immunogenicity. We report that ERK2 phosphorylation, an event preceding and required for NF-κB activation, occurred rapidly after virus infection. ERK2 and NF-κB remained inert when virus endocytosis was prevented, suggesting that virus-host cell interactions were insufficient for activating NF-κB. Inhibition of viral protein synthesis decreased NF-κB activation, and elimination of intermediate and late gene expression did not alter MVA-induced NF-κB activation. Thus, early gene expression activates NF-κB.
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