Infection of fibroblasts with a miR-UL22A mutant virus results in enhanced type I IFN production in a SMAD3- and IRF7-dependent manner and the virus is impaired for growth in the presence of TGFβ, but only when both SMAD3 and IRF7 are present, highlighting the unique interaction between TGFβ and innate immune signaling. Here, TGFB1 is linked to infection.