Single-cell analysis shows that paracrine signaling by first responder cells shapes the interferon-β response to...

Immune responses to viral infection are stochastic processes, which initiate in a limited number of cells that then propagate the response. A key component of the response to viral infection entails the synthesis and secretion of type I interferons (IFNs), including the early induction of the gene encoding IFN-β (Ifnb1). With single-cell analysis and mathematical modeling, we investigated the mechanisms underlying how increases in the amount of Ifnb1 mRNA per cell and in the numbers of cells expressing Ifnb1 calibrate the response to viral infection. We used single-cell, single-molecule assays to quantify the early induction of Ifnb1 expression (the Ifnb1 response) in human monocyte-derived dendritic cells infected with Newcastle disease virus, thus retaining the physiological stoichiometry of transcriptional regulators to both alleles of the Ifnb1 gene. We applied computational methods to extract the stochastic features that underlie the cell-to-cell variations in gene expression over time. Integration of simulations and experiments identified the role of paracrine signaling in increasing the number of cells that express Ifnb1 over time and in calibrating the immune response to viral infection.