Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state IV

Type I and III interferons (IFNs) are among the first lines of defense against viral infections, yet they are generally only produced by a tiny fraction of infected cells. Here, we show that variability in tonic cell signaling significantly influences cells’ ability to produce IFN upon stimulation with the synthetic double-stranded RNA, polyinosinic:polycytidylic acid (pIC). Using single-cell approaches, we found that members of the activator protein (AP)-1 transcription factor were implicated in IFNL1 expression predisposition. This guided us to investigate the role of the mitogen-activated protein kinase (MAPK) pathway, specifically the c-Jun N-terminal kinase (JNK), in IFNL1 production. We found that inhibition of JNK signaling severely altered the nature of the innate antiviral response upon pIC stimulation, independently of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Together, our study emphasizes the influence of intrinsic stochasticity in cell state on heterogeneity in IFN expression.