Abstract
Strict regulation of type I interferons (IFN) is vital for balancing tissue damage and protection against infections. We previously found that during Kaposi’s sarcoma-associated herpesvirus infection, type I IFN induction was limited to a small percentage of infected 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 similarly activated between cells that made high vs. low/no IFN-β. In contrast, the activation or expression of the two other IFN transcription factors, NF-κB and AP-1, correlated with IFN-β induction. Our results suggest that during viral infection, activation of IRF3 does not automatically result in IFN responses at the level of individual cells, but that other factors, such as NF-κB and AP-1, are limiting for type I IFN induction.
Importance
The ability of mammalian cells to react to viral infections is a crucial step in the induction of immune responses. The first course of action for the cell is to express and release type I interferons like interferon-β (IFN-β), secreted molecules that warn surrounding cells. Single-cell level examination of gene expression has revealed that surprisingly, during many viral infections, only a small fraction of infected cells makes IFN-β. This is likely a mechanism to prevent immune system overreactions. However, it remains unclear why only some cells respond. Here, we find that during infection with Kaposi’s sarcoma-associated herpesvirus, an oncogenic virus that affects immunocompromised individuals, the transcription factors AP-1 and NF-κB, rather than the more commonly studied IRF3, may decide which cells go on to make IFN-β. Our findings contribute to a better understanding of complex gene regulation and shed light on a process that fights an oncogenic virus.
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