Interferon-β induction heterogeneity during KSHV infection is determined by interferon-β enhanceosome transcription factors other than IRF3

Strict regulation of type I interferons (IFN) is vital for balancing tissue damage and immunity against infections. We previously found that during Kaposi’s sarcoma-associated herpesvirus infection, IFN induction was limited to a small percentage of infected B cells. This heterogeneity was not explained by viral gene expression. Here, we used a fluorescent reporter and fluorescence-activated cell sorting to investigate the source of this heterogeneity. Surprisingly, the canonical IFN induction pathway culminating in the activation of the IRF3 transcription factor was similar between cells that made high vs. low/no IFN-β. In contrast, the activation or expression of two other IFN transcription factors, NF-κB and AP-1, correlated with heterogeneous IFN-β induction. Our results suggest that at the level of individual cells, IRF3 is crucial as a pathogen detection signal, but NF-κB and AP-1 are limiting for IFN-β induction.